HIV inhibiting 5-carbo- or heterocyclic substituted pyrimidines

ABSTRACT

HIV replication inhibitors of formula (I) N-oxides, a pharmaceutically acceptable addition salts, a quaternary amines or a stereoisomeric forms thereof, wherein -a 1 =a 2 -a 3 =a 4 - is —CH═CH—CH═CH—, —N═CH—CH═CH—, —N═CH—N═CH—, —N═CH—CH═N—, —N═N—CH═CH—; -b 1 =b 2 -b 3 =b 4 - is —CH═CH—CH═CH—, —N═CH—CH═CH—, —N═CH—N═CH—, —N═CH—CH═N—, —N═N—CH═CH—; R 1  is hydrogen; aryl; formyl; C 1-6 alkylcarbonyl; optionally substituted C 1-6 alkyl; C 1-6 alkyloxycarbonyl; R 2  is OH; halo; optionally substituted C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl; substituted carbonyl; carboxyl; CN; nitro; amino; substituted amino; polyhalomethyl; polyhalomethylthio; —S(═O)rR 6 ; C(═NH)R 6 ; R 2a  is CN; amino; substituted amino; optionally substituted C 1-6 alkyl; halo; optionally substituted C 2-6 alkyloxy; substituted carbonyl; —CH═N—NH—C(═O)—R 16 ; optionally substituted C 1-6 alkyloxy C 1-6 alkyl; substituted C 2-6 alkenyl or C 2-6 alkynyl; —C(═N—O—R 8 )—C 1-4 alkyl; R 7  or —X 3 —R 7 ; X 1  is —NR 1 —, —O—, —C(═O)—, CH 2 , —CHOH—, —S—, —S(═O) r —; R 3  is CN; amino; C 1-6 alkyl; halo; optionally substituted C 1-6 alkyloxy; substituted carbonyl; —CH═N—NH—C(═O)—R 16 ; substituted C 1-6 alkyl; optionally substituted C 1-6 alkyloxy C 1-6 alkyl; substituted C 2-6 alkenyl or C 2-6 alkynyl; —C(═N—O—R 8 )—C 1-4 alkyl; R 7 ; —X 3 —R 7 ; R 4  is halo; OH; optionally substituted C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl; C 3-7 cycloalkyl; C 1-6 alkyloxy; CN; nitro; polyhalo C 1-6 alkyl; polyhalo C 1-6 alkyloxy; substituted carbonyl; formyl; amino; mono- or di(C 1-4 alkyl)amino or R 7 ; R 5  is —Y—C q H2 q -L or —C q H 2q —Y—C r H 2r -L; L is aryl or Het; processes for the preparation of these compounds, pharmaceutical compositions comprising these compounds as active ingredient and the use of these compounds for the prevention or the treatment of HIV infection.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a national stage application of Patent ApplicationNo. PCT/EP2005/054931, filed Sep. 29, 2005, which application claimspriority from EPO Patent Application No. 04104814.1, filed Sep. 30,2004, both of which are hereby incorporated by reference in theirentirety.

The present invention is concerned with pyrimidine derivatives havingHIV (Human Immunodeficiency Virus) replication inhibiting properties.The invention further relates to methods for their preparation andpharmaceutical compositions comprising them. The invention also relatesto the use of said compounds in the prevention or the treatment of HIVinfection.

Resistance of the HIV virus against currently available HIV drugscontinues to be a major cause of therapy failure. This has led to theintroduction of combination therapy of two or more anti-HIV agentsusually having a different activity profile. Significant progress wasmade by the introduction of HAART therapy (Highly Active Anti-RetroviralTherapy), which has resulted in a significant reduction of morbidity andmortality in HIV patient populations treated therewith. HAART involvesvarious combinations of nucleoside reverse transcriptase inhibitors(NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) andprotease inhibitors (PIs). Current guidelines for antiretroviral therapyrecommend such triple combination therapy regimen for initial treatment.However, these multidrug therapies do not completely eliminate HIV andlong-term treatment usually results in multidrug resistance. Inparticular, half of the patients receiving anti-HIV combination therapydo not respond fully to the treatment, mainly because of resistance ofthe virus to one or more drugs used. It also has been shown thatresistant virus is carried over to newly infected individuals, resultingin severely limited therapy options for these drug-naive patients.

Therefore there is a continued need for new combinations of activeingredients that are effective against HIV. New types of anti-HIVeffective active ingredients, differing in chemical structure andactivity profile are useful in new types of combination therapy Findingsuch active ingredients therefore is a highly desirable goal to achieve.

The present invention is aimed at providing particular novel series ofpyrimidine derivatives having HIV replication inhibiting properties. WO99/50250, WO 00/27825 and WO 01/85700 disclose certain substitutedaminopyrimidines and WO 99/50256 and EP-834 507 disclose aminotriazineshaving HIV replication inhibiting properties.

The compounds of the invention differ from prior art compounds instructure, pharmacological activity and/or pharmacological potency. Ithas been found that the introduction of carbocyclic or heterocyclicgroups linked to the 5-position of specifically substituted pyrimidinesresults in compounds the compounds not only acting favorably in terms oftheir capability to inhibit the replication of Human ImmunodeficiencyVirus (HIV), but also by their improved ability to inhibit thereplication of mutant strains, in particular strains which have becomeresistant to one or more known NNRTI drugs (Non Nucleoside ReverseTranscriptase Inhibitor drugs), which strains are referred to as drug ormultidrug resistant HIV strains.

Thus in one aspect, the present invention concerns a compound of formula

a N-oxide, a pharmaceutically acceptable addition salt, a quaternaryamine or a stereochemically isomeric form thereof, wherein

-   -a¹=a²-a³=a⁴- represents a bivalent radical of formula    —CH═CH—CH═CH—  (a-1);    —N═CH—CH═CH—  (a-2);    —N═CH—N═CH—  (a-3);    —N═CH—CH═N—  (a-4);    —N═N—CH═CH—  (a-5);-   -b¹=b²-b³=b⁴- represents a bivalent radical of formula    —CH═CH—CH═CH—  (b-1);    —N═CH—CH═CH—  (b-2);    —N═CH—N═CH—  (b-3);    —N═CH—CH═N—  (b-4);    —N═N—CH═CH—  (b-5);-   n is 0, 1, 2, 3 and in case -a¹=a²-a³=a⁴- is (a-1), then n may also    be 4;-   m is 0, 1, 2, 3 and in case -b¹=b²-b³=b⁴- is (b-1), then m may also    be 4;-   each R¹ independently is hydrogen; aryl; formyl; C₁₋₆alkylcarbonyl;    C₁₋₆alkyl; C₁₋₆alkyloxycarbonyl; C₁₋₆alkyl substituted with formyl,    C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl, or with    C₁₋₆alkylcarbonyloxy;-   each R² independently is hydroxy; halo; C₁₋₆alkyl optionally    substituted with one, two or three substituents each independently    selected from halo, cyano or —C(═O)R⁶; C₃₋₇cycloalkyl; C₂₋₆alkenyl    optionally substituted with one, two or three substituents each    independently selected from halo, cyano or —C(═O)R⁶; C₂₋₆alkynyl    optionally substituted with one, two or three substituents each    independently selected from halo, cyano or —C(═O)R⁶;    C₁₋₆alkyloxycarbonyl; carboxyl; cyano; nitro; amino; mono- or    di(C₁₋₆alkyl)amino; polyhalomethyl; polyhalomethylthio; —S(═O)rR⁶;    —NH—S(═O)rR⁶; —C(═O)R⁶; —NHC(═O)H; —C(═O)NHNH₂; NHC(═O)R⁶; C(═NH)R⁶;-   R^(2a) is cyano; aminocarbonyl; amino; C₁₋₆alkyl; halo; C₁₋₆alkyloxy    wherein C₁₋₆alkyl may optionally be substituted with cyano; NHR¹³;    NR¹³R¹⁴; —C(═O)—NHR¹³; —C(═O)—NR¹³R¹⁴; —C(═O)—R¹⁵;    —CH═N—NH—C(═O)—R¹⁶; C₁₋₆alkyl substituted with one, two or three    substituents each independently selected from halo, cyano, NR⁹R¹⁰,    —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl or R⁷; C₁₋₆alkyl substituted with    hydroxy and a second substituent selected from halo, cyano, NR⁹R¹⁰,    —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl or R⁷; C₁₋₆alkyloxyC₁₋₆alkyl    optionally substituted with one, two or three substituents each    independently selected from halo, cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰,    —C(═O)—C₁₋₆alkyl or R⁷; C₂₋₆alkenyl substituted with one, two or    three substituents each independently selected from halo, cyano,    NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl or R⁷; C₂₋₆alkynyl    substituted with one, two or three substituents each independently    selected from halo, cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl    or R⁷; —C(═N—O—R⁸)—C₁₋₄alkyl; R⁷ or —X₃—R⁷;-   X₁ is —NR¹—, —O—, —C(═O)—, —CH₂—, —CHOH—, —S—, —S(═O)r-,;-   R³ is cyano; aminocarbonyl; amino; C₁₋₆alkyl; halo; C₁₋₆alkyloxy    wherein C₁₋₆alkyl may optionally be substituted with cyano; NHR¹³;    NR¹³R¹⁴; —C(═O)—NHR¹³; —C(═O)—NR¹³R¹⁴; —C(═O)—R¹⁵;    —CH═N—NH—C(═O)—R¹⁶; C₁₋₆alkyl substituted with one, two or three    substituents each independently selected from halo, cyano, NR⁹R¹⁰,    —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl or R⁷; C₁₋₆alkyl substituted with    hydroxy and a second substituent selected from halo, cyano, NR⁹R¹⁰,    —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl or R⁷; C₁₋₆alkyloxyC₁₋₆alkyl    optionally substituted with one, two or three substituents each    independently selected from halo, cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰,    —C(═O)—C₁₋₆alkyl or R⁷; C₂₋₆alkenyl substituted with one, two or    three substituents each independently selected from halo, cyano,    NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl or R⁷; C₂₋₆alkynyl    substituted with one, two or three substituents each independently    selected from halo, cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl    or R⁷; —C(═N—O—R⁸)—C₁₋₄alkyl; R⁷ or —X₃—R⁷;-   X₃ is —NR¹—, —O—, —C(═O)—, —S—, —S(═O)_(r)—;-   R⁴ is halo; hydroxy; C₁₋₆alkyl optionally substituted with one, two    or three substituents each independently selected from halo, cyano    or —C(═O)R⁶; C₂₋₆alkenyl optionally substituted with one, two or    three substituents each independently selected from halo, cyano or    —C(═O)R⁶; C₂₋₆alkynyl optionally substituted with one, two or three    substituents each independently selected from halo, cyano or    —C(═O)R⁶; C₃₋₇cycloalkyl; C₁₋₆alkyloxy; cyano; nitro;    polyhaloC₁₋₆alkyl; polyhaloC₁₋₆alkyloxy; aminocarbonyl; mono- or    di(C₁₋₄alkyl)aminocarbonyl; C₁₋₆alkyloxycarbonyl; C₁₋₆alkylcarbonyl;    formyl; amino; mono- or di(C₁₋₄alkyl)amino or R⁷;-   R⁵ is a radical of formula —Y-Alk-L, -Alk′-Y-L or -Alk′-Y-Alk-L;-   each Alk or Alk′ independently is a bivalent C₁₋₆alkyl or    C₂₋₆alkenyl group;-   L is aryl or Het;-   Y is O, S, —S(═O)_(r)—, NR¹; —CH═N—O—;-   Het is a 5- or 6-membered completely unsaturated ring system wherein    one, two, three or four ring members are hetero atoms each    independently selected from the group consisting of nitrogen, oxygen    and sulfur, and wherein the remaining ring members are carbon atoms;    and, where possible, any nitrogen ring member may optionally be    substituted with C₁₋₆alkyl; which ring system may optionally be    annelated with a benzene ring; and wherein any ring carbon atom,    including any carbon of an optionally annelated benzene ring, may,    each independently, optionally be substituted with a substituent    selected from halo, hydroxy, mercapto, cyano, C₁₋₆alkyl,    hydroxyC₁₋₄alkyl, carboxyC₁₋₄alkyl, C₁₋₄alkyloxyC₁₋₄alkyl,    C₁₋₄alkyloxycarbonylC₁₋₄alkyl, cyanoC₁₋₄alkyl, mono- and    di(C₁₋₄alkyl)aminoC₁₋₄alkyl, Het¹C₁₋₄alkyl, arylC₁₋₄alkyl,    polyhaloC₁₋₄alkyl, C₃₋₇cycloalkyl, C₂₋₆alkenyl, aryl-C₂₋₄alkenyl,    C₁₋₄alkyloxy, —OCONH₂, polyhalo-C₁₋₄alkyloxy, aryloxy, amino, mono-    and di-C₁₋₄alkylamino, pyrrolidinyl, piperidinyl, morpholinyl,    piperazinyl, 4-C₁₋₆alkylpiperazinyl, C₁₋₄alkylcarbonylamino, formyl,    C₁₋₄alkylcarbonyl, C₁₋₄alkyloxy-carbonyl, aminocarbonyl, mono- and    diC₁₋₄alkylaminocarbonyl, aryl, Het¹;-   Het¹ is pyridyl, thienyl, furanyl, oxazolyl, isoxazolyl, imidazolyl,    pyrazolyl, thiazolyl, thiadiazolyl, oxadiazolyl quinolinyl,    benzothienyl, benzofuranyl; which each may optionally be substituted    with one or two C₁₋₄alkyl radicals;-   Q is hydrogen, C₁₋₆alkyl, halo, polyhaloC₁₋₆alkyl, or —NR⁹R¹⁰;-   R⁶ is C₁₋₄alkyl, amino, mono- or di(C₁₋₄alkyl)amino or    polyhaloC₁₋₄alkyl;-   R⁷ is a monocyclic, bicyclic or tricyclic saturated, partially    saturated or aromatic carbocycle or a monocyclic, bicyclic or    tricyclic saturated, partially saturated or aromatic heterocycle,    wherein each of said carbocyclic or heterocyclic ring systems may    optionally be substituted with one, two, three, four or five    substituents each independently selected from halo, hydroxy,    mercapto, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl, mono or    di(C₁₋₆alkyl)aminoC₁₋₆alkyl, formyl, C₁₋₆alkylcarbonyl,    C₃₋₇cycloalkyl, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylthio,    cyano, nitro, polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy,    aminocarbonyl, —CH(═N—O—R⁸), R^(7a), —X₃—R^(7a) or    R^(7a)—C₁₋₄alkyl-;-   R^(7a) is a monocyclic, bicyclic or tricyclic saturated, partially    saturated or aromatic carbocycle or a monocyclic, bicyclic or    tricyclic saturated, partially saturated or aromatic heterocycle,    wherein each of said carbocyclic or heterocyclic ring systems may    optionally be substituted with one, two, three, four or five    substituents each independently selected from halo, hydroxy,    mercapto, C₁₋₆alkyl, hydroxy C₁₋₆alkyl, aminoC₁₋₆alkyl, mono or    di(C₁₋₆alkyl)aminoC₁₋₆alkyl, formyl, C₁₋₆alkylcarbonyl,    C₃₋₇cycloalkyl, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylthio,    cyano, nitro, polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy,    aminocarbonyl, —CH(═N—O—R⁸);-   R⁸ is hydrogen, C₁₋₄alkyl, aryl or arylC₁₋₄alkyl;-   R⁹ and R¹⁰ each independently are hydrogen; C₁₋₆alkyl;    C₁₋₆alkylcarbonyl; C₁₋₆alkyloxycarbonyl; amino; mono- or    di(C₁₋₆alkyl)aminocarbonyl; —CH(═NR¹¹) or R⁷, wherein each of the    aforementioned C₁₋₆alkyl groups may optionally and each individually    be substituted with one or two substituents each independently    selected from hydroxy, C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy, carboxyl,    C₁₋₆alkyloxycarbonyl, cyano, amino, imino, mono- or    di(C₁₋₄alkyl)amino, polyhalomethyl, polyhalomethyloxy,    polyhalomethylthio, —S(═O) r R⁶, —NH—S(═O) r R⁶, —C(═O)R⁶,    —NHC(═O)H, —C(═O)NHNH₂, —NHC(═O)R⁶, —C(═NH)R⁶, R⁷; or-   R⁹ and R¹⁰ may be taken together to form a bivalent or trivalent    radical of formula    —CH₂—CH₂—CH₂—CH₂—  (d-1)    —CH₂—CH₂—CH₂—CH₂—CH₂—  (d-2)    —CH₂—CH₂—O—CH₂—CH₂—  (d-3)    —CH₂—CH₂—S—CH₂—CH₂—  (d-4)    —CH₂—CH₂—NR¹²—CH₂—CH₂—  (d-5)    —CH₂—CH═CH—CH₂—  (d-6)    ═CH—CH═CH—CH═CH—  (d-7)-   R¹¹ is cyano; C₁₋₄alkyl optionally substituted with C₁₋₄alkyloxy,    cyano, amino, mono- or di(C₁₋₄alkyl)amino or aminocarbonyl;    C₁₋₄alkylcarbonyl; C₁₋₄alkyloxycarbonyl; aminocarbonyl; mono- or    di(C₁₋₄alkyl)aminocarbonyl;-   R¹² is hydrogen or C₁₋₄alkyl;-   R¹³ and R¹⁴ each independently are C₁₋₆alkyl optionally substituted    with cyano or aminocarbonyl, C₂₋₆alkenyl optionally substituted with    cyano or aminocarbonyl, C₂₋₆alkynyl optionally substituted with    cyano or aminocarbonyl;-   R¹⁵ is C₁₋₆alkyl substituted with cyano or aminocarbonyl;-   R¹⁶ is C₁₋₆alkyl optionally substituted with cyano or aminocarbonyl,    or R⁷;-   each r is 1 or 2;-   each aryl is phenyl or phenyl substituted with one, two, three, four    or five substituents each independently selected from halo, hydroxy,    mercapto, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, hydroxyC₁₋₆alkyl,    aminoC₁₋₆alkyl, mono or di(C₁₋₆alkyl)amino-C₁₋₆alkyl,    C₁₋₆alkylcarbonyl, C₃₋₇cycloalkyl, C₁₋₆alkyloxy, phenylC₁₋₆alkyloxy,    C₁₋₆alkyloxycarbonyl, aminosulfonyl, C₁₋₆alkylthio, cyano, nitro,    polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy, aminocarbonyl, phenyl, Het¹    or —X₃-Het¹.

The present invention also relates to the use of a compound for themanufacture of a medicament for the treatment or prevention of HIVinfection, wherein the compound has the formula (I) as specified herein.

As used hereinbefore or hereinafter C₁₋₄alkyl as a group or part of agroup defines straight or branched chain saturated hydrocarbon radicalshaving from 1 to 4 carbon atoms such as methyl, ethyl, propyl,1-methylethyl, butyl; C₁₋₆alkyl as a group or part of a group definesstraight or branched chain saturated hydrocarbon radicals having from 1to 6 carbon atoms such as the group defined for C₁₋₄alkyl and pentyl,hexyl, 2-methylbutyl and the like; C₂₋₆alkyl as a group or part of agroup defines straight or branched chain saturated hydrocarbon radicalshaving from 2 to 6 carbon atoms such as ethyl, propyl, 1-methylethyl,butyl, pentyl, hexyl, 2-methylbutyl and the like; C₃₋₇cycloalkyl isgeneric to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andcycloheptyl; C₂₋₆alkenyl defines straight and branched chain hydrocarbonradicals having from 2 to 6 carbon atoms containing a double bond suchas ethenyl, propenyl, butenyl, pentenyl, hexenyl and the like;C₂₋₆alkynyl defines straight and branched chain hydrocarbon radicalshaving from 2 to 6 carbon atoms containing a triple bond such asethynyl, propynyl, butynyl, pentynyl, hexynyl and the like. Of interestamongst the C₂₋₆alkenyl and C₂₋₆alkynyl groups are the unsaturatedanalogs having from 2 to 4 carbon atoms, i.e. C₂₋₄alkenyl andC₂₋₄alkynyl respectively. C₂₋₆alkenyl and C₂₋₆alkynyl groups that arelinked to a heteroatom are preferably linked to that atom via asaturated carbon atom and thereby are limited to C₃₋₆alkenyl andC₃₋₆alkynyl groups.

The term “bivalent C₁₋₆alkyl or C₂₋₆alkenyl” refers to bivalent radicalswhich otherwise can also be referred to as C₁₋₆alkanediyl orC₂₋₆alkenediyl. The term bivalent C₁₋₆alkyl or C₁₋₆alkanediyl definesstraight or branched chain saturated bivalent hydrocarbon radicalshaving from 1 to 6 carbon atoms such as methylene, 1,2-ethanediyl or1,2-ethylene, 1,3-propanediyl or 1,3-propylene, 1,2-propanediyl or1,2-propylene, 1,4-butanediyl or 1,4-butylene, 1,3-butanediyl or1,3-butylene, 1,2-butanediyl or 1,2-butylene, 1,5-pentanediyl or1,5-pentylene, 1,6-hexanediyl or 1,6-hexylene, etc., also including thealkylidene radicals such as ethylidene, propylidene and the like. Theterm bivalent C₁₋₄alkyl or C₁₋₄alkanediyl defines the analogous straightor branched chain saturated bivalent hydrocarbon radicals having from 1to 4 carbon atoms. The term bivalent C₂₋₆alkenyl or C₂₋₆alkenediyldefines straight or branched chain bivalent hydrocarbon radicals havingfrom 1 to 6 carbon atoms and having one or more (e.g. one, two, three)and preferably one double bond such as ethene-1,2-diyl,propene-1,3-diyl, propene-1,2-diyl, butene-1,4-diyl, 2-butene-1,4-diyl,butene-1,3-diyl, butene-3,4-diyl, butene-4,4-diyl, pentene-1,5-diyl,2-pentene-1,5-diyl, hexene-1,6-diyl, 2-hexene-1,6-diyl,3-hexene-1,6-diyl, etc. The term bivalent C₃₋₆alkenyl or C₃₋₆alkenediyldefines the analogous straight or branched chain bivalent unsaturatedhydrocarbon radicals having from 3 to 6 carbon atoms while the termbivalent C₃₋₄alkenyl or C₃₋₄alkenediyl defines the analogous straight orbranched chain bivalent unsaturated hydrocarbon radicals having from 3to 4 carbon atoms. Of particular interest are bivalent C₃₋₆alkenyl orbivalent C₃₋₄alkenyl radicals, in particular those wherein the carbonatom linked to a heteroatom is a saturated carbon atom.

In a number of instances the radicals C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl or C₁₋₆alkyloxyC₁₋₆alkyl may be substituted with one, two orthree substituents. Preferably, said radicals are substituted with up to2 substituents, more preferably with one substituent.

A monocyclic, bicyclic or tricyclic saturated carbocycle represents aring system consisting of 1, 2 or 3 rings, said ring system beingcomposed of only carbon atoms and said ring system containing onlysingle bonds; a monocyclic, bicyclic or tricyclic partially saturatedcarbocycle represents a ring system consisting of 1, 2 or 3 rings, saidring system being composed of only carbon atoms and comprising at leastone double bond provided that the ring system is not an aromatic ringsystem; a monocyclic, bicyclic or tricyclic aromatic carbocyclerepresents an aromatic ring system consisting of 1, 2 or 3 rings, saidring system being composed of only carbon atoms; the term aromatic iswell known to a person skilled in the art and designates cyclicallyconjugated systems of 4n+2 electrons, that is with 6, 10, 14 etc.π-electrons (rule of Hückel); a monocyclic, bicyclic or tricyclicsaturated heterocycle represents a ring system consisting of 1, 2 or 3rings and comprising at least one heteroatom selected from O, N or S,said ring system containing only single bonds; a monocyclic, bicyclic ortricyclic partially saturated heterocycle represents a ring systemconsisting of 1, 2 or 3 rings and comprising at least one heteroatomselected from O, N or S, and at least one double bond provided that thering system is not an aromatic ring system; a monocyclic, bicyclic ortricyclic aromatic heterocycle represents an aromatic ring systemconsisting of 1, 2 or 3 rings and comprising at least one heteroatomselected from O, N or S.

Particular examples of monocyclic, bicyclic or tricyclic saturatedcarbocycles are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, bicyclo[4,2,0]octanyl, cyclononanyl,cyclodecanyl, decahydronapthalenyl, tetradecahydroanthracenyl and thelike. Preferred are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl; more preferred are cyclopentyl, cyclohexyl, cycloheptyl.

Particular examples of monocyclic, bicyclic or tricyclic partiallysaturated carbocycles are cyclopropenyl, cyclobutenyl, cyclopentenyl,cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclo[4,2,0]octenyl,cyclononenyl, cyclodecenyl, octahydronaphthalenyl,1,2,3,4-tetrahydronaphthalenyl, 1,2,3,4,4a,9,9a,10-octahydro-anthracenyland the like.

Particular examples of monocyclic, bicyclic or tricyclic aromaticcarbocycles are phenyl, naphthalenyl, anthracenyl. Preferred is phenyl.

Particular examples of monocyclic, bicyclic or tricyclic saturatedheterocycles are tetrahydrofuranyl, pyrrolidinyl, dioxolanyl,imidazolidinyl, thiazolidinyl, tetrahydrothienyl, dihydrooxazolyl,isothiazolidinyl, isoxazolidinyl, oxadiazolidinyl, triazolidinyl,thiadiazolidinyl, pyrazolidinyl, piperidinyl, hexahydropyrimidinyl,hexahydropyrazinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl,piperazinyl, trithianyl, decahydroquinolinyl, octahydroindolyl and thelike. Preferred are tetrahydrofuranyl, pyrrolidinyl, dioxolanyl,imidazolidinyl, thiazolidinyl, dihydrooxazolyl, triazolidinyl,piperidinyl, dioxanyl, morpholinyl, thiomorpholinyl, piperazinyl.Particularly preferred are tetrahydrofuranyl, pyrrolidinyl, dioxolanyl,piperidinyl, dioxanyl, morpholinyl, thiomorpholinyl, piperazinyl.

Particular examples of monocyclic, bicyclic or tricyclic partiallysaturated heterocycles are pyrrolinyl, imidazolinyl, pyrazolinyl,2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl,2,3-dihydro-1,4-benzodioxinyl, indolinyl and the like. Preferred arepyrrolinyl, imidazolinyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl,indolinyl.

Particular examples of monocyclic, bicyclic or tricyclic aromaticheterocycles are azetyl, oxetylidenyl, pyrrolyl, furyl, thienyl,imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl,triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidinyl,pyrazinyl, pyridazinyl, triazinyl, pyranyl, benzofuryl, isobenzofuryl,benzothienyl, isobenzothienyl, indolizinyl, indolyl, isoindolyl,benzoxazolyl, benzimidazolyl, indazolyl, benzisoxazolyl,benzisothiazolyl, benzopyrazolyl, benzoxadiazolyl, benzothiadiazolyl,benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl,quinolizinyl, phthalazinyl, quinoxalinyl, quinazolinyl, naphthiridinyl,pteridinyl, benzopyranyl, pyrrolopyridyl, thienopyridyl, furopyridyl,isothiazolopyridyl, thiazolopyridyl, isoxazolopyridyl, oxazolopyridyl,pyrazolopyridyl, imidazopyridyl, pyrrolopyrazinyl, thienopyrazinyl,furopyrazinyl, isothiazolopyrazinyl, thiazolopyrazinyl,isoxazolopyrazinyl, oxazolopyrazinyl, pyrazolopyrazinyl,imidazopyrazinyl, pyrrolopyrimidinyl, thienopyrimidinyl,furopyrimidinyl, isothiazolopyrimidinyl, thiazolopyrimidinyl,isoxazolopyrimidinyl, oxazolopyrimidinyl, pyrazolopyrimidinyl,imidazopyrimidinyl, pyrrolopyridazinyl, thienopyridazinyl,furopyridazinyl, isothiazolopyridazinyl, thiazolopyridazinyl,isoxazolopyridazinyl, oxazolopyridazinyl, pyrazolopyridazinyl,imidazopyridazinyl, oxadiazolopyridyl, thiadiazolopyridyl,triazolopyridyl, oxadiazolopyrazinyl, thiadiazolopyrazinyl,triazolopyrazinyl, oxadiazolopyrimidinyl, thiadiazolopyrimidinyl,triazolopyrimidinyl, oxadiazolopyridazinyl, thiadiazolopyridazinyl,triazolopyridazinyl, imidazooxazolyl, imidazothiazolyl,imidazoimidazolyl, isoxazolotriazinyl, isothiazolotriazinyl,pyrazolotriazinyl, oxazolotriazinyl, thiazolotriazinyl,imidazotriazinyl, oxadiazolotriazinyl, thiadiazolotriazinyl,triazolotriazinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl,phenoxazinyl and the like.

Preferred aromatic heterocycles are monocyclic or bicyclic aromaticheterocycles. Interesting monocyclic, bicyclic or tricyclic aromaticheterocycles are pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, thiadiazolyl,oxadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,triazinyl, pyranyl, benzofuryl, isobenzofuryl, benzothienyl,isobenzothienyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl,indazolyl, benzisoxazolyl, benzisothiazolyl, benzopyrazolyl,benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl,isoquinolinyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzopyranyl,pyrrolopyridyl, thienopyridyl, furopyridyl, isothiazolopyridyl,thiazolopyridyl, isoxazolopyridyl, oxazolopyridyl, pyrazolopyridyl,imidazopyridyl, pyrrolopyrazinyl, thienopyrazinyl, furopyrazinyl,isothiazolopyrazinyl, thiazolopyrazinyl, isoxazolopyrazinyl,oxazolopyrazinyl, pyrazolopyrazinyl, imidazopyrazinyl,pyrrolopyrimidinyl, thienopyrimidinyl, furopyrimidinyl,isothiazolopyrimidinyl, thiazolopyrimidinyl, isoxazolopyrimidinyl,oxazolopyrimidinyl, pyrazolopyrimidinyl, imidazopyrimidinyl,oxadiazolopyridyl, thiadiazolopyridyl, triazolopyridyl,oxadiazolopyrazinyl, thiadiazolopyrazinyl, triazolopyrazinyl,oxadiazolopyrimidinyl, thiadiazolopyrimidinyl, triazolopyrimidinyl,carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl and the like.

Particularly interesting aromatic heterocycles are pyrrolyl, furyl,thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl,pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyranyl, benzofuryl,isobenzofuryl, benzothienyl, isobenzothienyl, indolyl, isoindolyl,benzoxazolyl, benzimidazolyl, indazolyl, benzisoxazolyl,benzisothiazolyl, benzopyrazolyl, benzoxadiazolyl, benzothiadiazolyl,benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, phthalazinyl,quinoxalinyl, quinazolinyl, and the like.

As used herein before, the term (═O) forms a carbonyl moiety whenattached to a carbon atom, a sulfoxide moiety when attached to a sulfuratom and a sulfonyl moiety when two of said terms are attached to asulfur atom.

The terms carboxyl, carboxy or hydroxycarbonyl refer to a group —COOH.

The term halo is generic to fluoro, chloro, bromo and iodo. As used inthe foregoing and hereinafter, polyhalomethyl as a group or part of agroup is defined as mono- or polyhalosubstituted methyl, in particularmethyl with one or more fluoro atoms, for example, difluoromethyl ortrifluoromethyl; polyhaloC₁₋₄alkyl or polyhaloC₁₋₆alkyl as a group orpart of a group is defined as mono- or polyhalosubstituted C₁₋₄alkyl orC₁₋₆alkyl, for example, the groups defined in halomethyl,1,1-difluoro-ethyl and the like. In case more than one halogen atoms areattached to an alkyl group within the definition of polyhalomethyl,polyhaloC₁₋₄alkyl or polyhaloC₁₋₆alkyl, they may be the same ordifferent.

The radical Het is a 5- or 6-membered completely unsaturated ring systemwhich may be annelated with a benzene ring as specified herein. The termcompletely unsaturated as used in this definition means that the ringcontains the maximum number of double bonds. In many instances the said5- or 6-membered ring system will be aromatic. Particular subgroups ofcompounds in accordance with the present invention therefore are thosegroups or subgroups as defined herein wherein Het is a 5- or 6-memberedaromatic ring system as specified herein. The radical Het in particularmay be any of the heterocycles mentioned in the groups of monocyclic,bicyclic or tricycles specified above, that are covered by the generaldefinition of Het, e.g. pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, thiadiazolyl,oxadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,triazinyl, pyranyl, benzofuryl, isobenzofuryl, benzothienyl,isobenzothienyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl,indazolyl, benzisoxazolyl, benzisothiazolyl, benzopyrazolyl,benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, quinolinyl,isoquinolinyl, cinnolinyl, phthalazinyl, quinoxalinyl, quinazolinyl,naphthiridinyl, benzopyranyl.

The radical Het can be substituted with pyrrolidinyl, piperidinyl,morpholinyl, piperazinyl, 4-C₁₋₆alkylpiperazinyl. Preferably, theseradicals are linked to the Het moiety via their nitrogen atom.

Whenever it occurs in the definition of the compounds of formula (I) orin any of the subgroups specified herein, each aryl independently is asdefined above in the definition of the compounds of formulas (I) or eacharyl can have any of the meanings specified hereinafter, in particularunder the limitations (22), (22a), etc.

The term heterocycle in the definition of R⁷ or R^(7a) is meant toinclude all the possible isomeric forms of the heterocycles, forinstance, pyrrolyl comprises 1H-pyrrolyl and 2H-pyrrolyl.

The carbocycle or heterocycle in the definition of R⁷ or R^(7a) may beattached to the remainder of the molecule of formula (I) through anyring carbon or heteroatom as appropriate, if not otherwise specified.Thus, for example, when the heterocycle is imidazolyl, it may be1-imidazolyl, 2-imidazolyl, 4-imidazolyl and the like, or when thecarbocycle is naphthalenyl, it may be 1-naphthalenyl, 2-naphthalenyl andthe like.

When any variable (e.g. R⁷, X₂) occurs more than one time in anyconstituent, each definition of such variable is independent.

Any of the restrictions in the definitions of the radicals herein aremeant to be applicable to the group of compounds of formula (I) as wellas to any subgroup defined or mentioned herein.

Lines drawn from substituents into ring systems indicate that the bondmay be attached to any of the suitable ring atoms.

For therapeutic use, salts of the compounds of formula (I) are thosewherein the counter ion is pharmaceutically acceptable. However, saltsof acids and bases which are non-pharmaceutically acceptable may alsofind use, for example, in the preparation or purification of apharmaceutically acceptable compound. All salts, whetherpharmaceutically acceptable or not are included within the ambit of thepresent invention.

The pharmaceutically acceptable addition salts as mentioned hereinaboveare meant to comprise the therapeutically active non-toxic acid additionsalt forms which the compounds of formula (I) are able to form. Thelatter can conveniently be obtained by treating the base form with suchappropriate acids as inorganic acids, for example, hydrohalic acids,e.g. hydrochloric, hydrobromic and the like; sulfuric acid; nitric acid;phosphoric acid and the like; or organic acids, for example, acetic,propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, oxalic,malonic, succinic, maleic, fumaric, malic, tartaric,2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic,benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic,2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids.Conversely the salt form can be converted by treatment with alkali intothe free base form.

The compounds of formula (I) containing acidic protons may be convertedinto their therapeutically active non-toxic metal or amine addition saltforms by treatment with appropriate organic and inorganic bases.Appropriate base salt forms comprise, for example, the ammonium salts,the alkali and earth alkaline metal salts, e.g. the lithium, sodium,potassium, magnesium, calcium salts and the like, salts with organicbases, e.g. primary, secondary and tertiary aliphatic and aromaticamines such as methylamine, ethylamine, propylamine, isopropylamine, thefour butylamine isomers, dimethylamine, diethylamine, diethanolamine,dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine,piperidine, morpholine, trimethylamine, triethylamine, tripropylamine,quinuclidine, pyridine, quinoline and isoquinoline, the benzathine,N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3-propanediol,hydrabamine salts, and salts with amino acids such as, for example,arginine, lysine and the like. Conversely the salt form can be convertedby treatment with acid into the free acid form. The term addition saltalso comprises the hydrates and solvent addition forms which thecompounds of formula (I) are able to form. Examples of such forms aree.g. hydrates, alcoholates and the like.

The term “quaternary amine” as used hereinbefore defines the quaternaryammonium salts which the compounds of formula (I) are able to form byreaction between a basic nitrogen of a compound of formula (I) and anappropriate quaternizing agent, such as, for example, an optionallysubstituted alkylhalide, arylhalide or arylalkylhalide, e.g.methyliodide or benzyliodide. Other reactants with good leaving groupsmay also be used, such as alkyl trifluoromethanesulfonates, alkylmethanesulfonates, and alkyl p-toluenesulfonates. A quaternary amine hasa positively charged nitrogen. Pharmaceutically acceptable counterionsinclude chloro, bromo, iodo, trifluoroacetate and acetate. Thecounterion of choice can be introduced using ion exchange resins.

The N-oxide forms of the present compounds are meant to comprise thecompounds of formula (I) wherein one or several tertiary nitrogen atomsare oxidized to the so-called N-oxide.

It will be appreciated that some of the compounds of formula (I) andtheir N-oxides, addition salts, quaternary amines and stereochemicallyisomeric forms may contain one or more centers of chirality and exist asstereochemically isomeric forms.

The term “stereochemically isomeric forms” as used hereinbefore definesall the possible stereoisomeric forms which the compounds of formula(I), and their N-oxides, addition salts, quaternary amines orphysiologically functional derivatives may possess. Unless otherwisementioned or indicated, the chemical designation of compounds denotesthe mixture of all possible stereochemically isomeric forms, saidmixtures containing all diastereomers and enantiomers of the basicmolecular structure as well as each of the individual isomeric forms offormula (I) and their N-oxides, salts, solvates or quaternary aminessubstantially free, i.e. associated with less than 10%, preferably lessthan 5%, in particular less than 2% and most preferably less than 1% ofthe other isomers. Thus, when a compound of formula (I) is for instancespecified as (E), this means that the compound is substantially free ofthe (Z) isomer. In particular, stereogenic centers may have the R- orS-configuration; substituents on bivalent cyclic (partially) saturatedradicals may have either the cis- or trans-configuration. Compoundsencompassing double bonds can have an E (entgegen) or Z(zusammen)-stereochemistry at said double bond. The terms cis, trans, R,S, E and Z are well known to a person skilled in the art.Stereochemically isomeric forms of the compounds of formula (I) areintended to be embraced within the scope of this invention.

Some of the compounds of formula (I) may also exist in their tautomericform. Such forms although not explicitly indicated in the above formulaare intended to be included within the scope of the present invention.

Whenever used hereinafter, the term “compounds of formula (I)” is meantto also include their N-oxide forms, their salts, their quaternaryamines and their stereochemically isomeric forms. Of special interestare those compounds of formula (I), which are stereochemically pure.

Particular subgroups of compounds of formula (I) or any of the subgroupsof compounds of formula (I) specified herein which are thenon-salt-forms, the salts, the N-oxide forms and stereochemicallyisomeric forms. Of interest amongst these are the non-salt-forms, thesalts and stereochemically isomeric forms. As used herein, the term‘non-salt-form’ refers to the form of a compound which is not a salt,which in most cases will be the free base form.

Whenever mention is made hereinbefore or hereinafter that substituentscan be selected each independently out of a list of numerousdefinitions, such as for example for R⁹ and R¹⁰, all possiblecombinations are intended which are chemically possible or which lead tochemically stable molecules.

It is to be understood that any of the subgroups of compounds offormulae (I) as defined herein, are meant to also comprise any prodrugs,N-oxides, addition salts, quaternary amines, metal complexes andstereochemically isomeric forms of such compounds. Any further subgroupcomprising a permutation of any of the more specific definitions ofsubgroups of compounds of formula (I) as mentioned hereafter, is meantto also form part of the disclosure of this invention.

Particular subgroups of the compounds of formula (I) are those compoundsof formula (I), or any subgroup of compounds of formula (I) specifiedherein, wherein -a¹=a²-a³=a⁴- is —CH═CH—CH═CH— (a-1);

Further subgroups of the compounds of formula (I) are those compounds offormula (I), or any subgroup of compounds of formula (I) specifiedherein, wherein -b¹=b²-b³=b⁴- is —CH═CH—CH═CH— (b-1).

Further subgroups of the compounds of formula (I) are those compounds offormula (I), or any subgroup of compounds of formula (I) specifiedherein, wherein (a) n is 0, 1, 2, 3; or wherein (b) n is 0, 1 or 2; or(c) n is 0.

Other subgroups of the compounds of formula (I) are those compounds offormula (I), or any subgroup of compounds of formula (I) specifiedherein, wherein (a) m is 0, 1, 2, 3; or wherein (b) m is 0, 1 or 2; or(c) m is 2.

Still further subgroups of the compounds of formula (I) are thosecompounds of formula (I), or any subgroup of compounds of formula (I)specified herein, wherein

-   (a) R¹ is hydrogen; formyl; C₁₋₆alkylcarbonyl; C₁₋₆alkyl;    C₁₋₆alkyloxycarbonyl; or-   (b) R¹ is hydrogen; C₁₋₆alkyl; or-   (c) R¹ is hydrogen.

Still further subgroups of the compounds of formula (I) are thosecompounds of formula (I), or any subgroup of compounds of formula (I)specified herein, wherein

-   (a) R² is hydroxy; halo; C₁₋₆alkyl optionally substituted with one    substituent selected from halo, cyano or —C(═O)R⁶; C₃₋₇cycloalkyl;    C₂₋₆alkenyl optionally substituted with one substituent selected    from halo, cyano or —C(═O)R⁶; C₂₋₆alkynyl optionally substituted    with one substituent selected from halo, cyano or —C(═O)R⁶;    C₁₋₆alkyloxycarbonyl; carboxyl; cyano; nitro; amino; mono- or    di(C₁₋₆alkyl)amino; polyhalomethyl; polyhalomethylthio;    —S(═O)_(p)R⁶; —NH—S(═O)_(p)R⁶; —C(═O)R⁶; —NHC(═O)H; —C(═O)NHNH₂;    NHC(═O)R⁶; C(═NH)R⁶;-   (b) R² is hydroxy; halo; C₁₋₆alkyl optionally substituted with one    substituent selected from halo, cyano or —C(═O)R⁶; C₂₋₆alkenyl    optionally substituted with one substituent selected from halo,    cyano or —C(═O)R⁶; C₂₋₆alkynyl optionally substituted with one    substituent selected from halo, cyano or —C(═O)R⁶;    C₁₋₆alkyloxycarbonyl; carboxyl; cyano; nitro; amino; mono- or    di(C₁₋₆alkyl)-amino; trifluoromethyl;-   (c) R¹ is halo, C₁₋₆alkyl optionally substituted with cyano,    C₂₋₆alkenyl optionally substituted with cyano, C₂₋₆alkynyl    optionally substituted with cyano, C₁₋₆alkyloxycarbonyl, carboxyl,    cyano, amino, mono(C₁₋₆alkyl)amino, di(C₁₋₆alkyl)amino;-   (d) R² is halo, cyano, aminocarbonyl, C₁₋₆alkyloxy, C₁₋₆alkyl,    C₁₋₆alkyl substituted with cyano or C₂₋₆alkenyl substituted with    cyano;-   (e) R² is halo, cyano, aminocarbonyl, C₁₋₄alkyl substituted with    cyano or C₂₋₄alkenyl substituted with cyano;-   (f) R² is cyano, aminocarbonyl; or (g) R² is cyano.

Still further subgroups of the compounds of formula (I) are thosecompounds of formula (I), or any subgroup of compounds of formula (I)specified herein, wherein

-   (a) R^(2a) is cyano; aminocarbonyl; amino; C₁₋₆alkyl; halo;    C₁₋₆alkyloxy wherein C₁₋₆alkyl may optionally be substituted with    cyano; NHR¹³; NR¹³R¹⁴; —C(═O)—NHR¹³; —C(═O)—NR¹³R¹⁴; —C(═O)—R⁵;    —CH═N—NH—C(═O)—R¹⁶; C₁₋₆alkyl substituted with one substituent    selected from halo, cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl    or R⁷; C₁₋₆alkyl substituted with hydroxy and a second substituent    selected from halo, cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl    or R⁷; C₁₋₆alkyloxyC₁₋₆alkyl optionally substituted with one    substituent selected from halo, cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰,    —C(═O)—C₁₋₆alkyl or R⁷; C₂₋₆alkenyl substituted with one substituent    selected from halo, cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl    or R⁷; C₂₋₆alkynyl substituted with one substituent selected from    halo, cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl or R⁷;    —C(═N—O—R⁸)—C₁₋₄alkyl; R⁷ or —X₃—R⁷;-   (b) R^(2a) is cyano; aminocarbonyl; amino; C₁₋₆alkyl; halo;    C₁₋₆alkyloxy wherein C₁₋₆alkyl may optionally be substituted with    cyano; NHR¹³; NR¹³R¹⁴; —C(═O)—NHR¹³; —C(═O)—NR¹³R¹⁴; —C(═O)—R¹⁵;    —CH═N—NH—C(═O)—R¹⁶; C₁₋₆alkyl substituted with one substituent    selected from halo, cyano, —C(═O)—NR⁹R¹⁰; C₁₋₆alkyl substituted with    hydroxy and a second substituent selected from halo, cyano,    —C(═O)—NR⁹R¹⁰; C₁₋₆alkyloxyC₁₋₆alkyl optionally substituted with one    substituent selected from halo, cyano, —C(═O)—NR⁹R¹⁰; C₂₋₆alkenyl    substituted with one substituent selected from halo, cyano,    —C(═O)—NR⁹R¹⁰; C₂₋₆alkynyl substituted with one substituent selected    from halo, cyano, —C(═O)—NR⁹R¹⁰;-   (c) R^(2a) is halo, cyano, aminocarbonyl, C₁₋₆alkyl optionally    substituted with cyano or aminocarbonyl, C₂₋₆alkenyl optionally    substituted with cyano or aminocarbonyl;-   (d) R^(2a) is halo, cyano, aminocarbonyl, C₁₋₆alkyl substituted with    cyano or aminocarbonyl, or C₂₋₆alkenyl substituted with cyano or    aminocarbonyl;-   (e) R^(2a) is cyano, aminocarbonyl, C₁₋₆alkyl substituted with cyano    or C₂₋₆alkenyl substituted with cyano;-   (f) R^(2a) is cyano, aminocarbonyl, C₁₋₄alkyl substituted with cyano    or C₂₋₄alkenyl substituted with cyano;-   (g) R^(2a) is cyano, C₁₋₄alkyl substituted with cyano or C₂₋₄alkenyl    substituted with cyano; or (h) R^(2a) is cyano.

Still further subgroups of the compounds of formula (I) are thosecompounds of formula (I), or any subgroup of compounds of formula (I)specified herein, wherein

-   (a) X₁ is —NR¹—, —O—, —S—, —S(═O)_(p)—;-   (b) X₁ is —NH—, —N(C₁₋₄alkyl)-, —O—, —S—, —S(═O)_(p)—;-   (c) X₁ is —NH—, —N(CH₃)—, —O—, —S—; (d) X₁ is —NH—, —O—, —S—;-   (e) X₁ is —NH—, —O—; or (f) X₁ is —NH—.

Still other subgroups of the compounds of formula (I) are thosecompounds of formula (I), or any subgroup of compounds of formula (I)specified herein, wherein

-   (a) R³ is cyano; aminocarbonyl; amino; C₁₋₆alkyl; halo; C₁₋₆alkyloxy    wherein C₁₋₆alkyl may optionally be substituted with cyano; NHR¹³;    NR¹³R¹⁴; —C(═O)—NHR¹³; —C(═O)—NR¹³R¹⁴; —C(═O)—R¹⁵; —CH═N—NH—C(═O)—R¹    6; C₁₋₆alkyl substituted with one substituent selected from halo,    cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl or R⁷; C₁₋₆alkyl    substituted with hydroxy and a second substituent selected from    halo, cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl or R⁷;    C₁₋₆alkyloxyC₁₋₆alkyl optionally substituted with one substituent    selected from halo, cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl    or R⁷; C₂₋₆alkenyl substituted with one substituent selected from    halo, cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl or R⁷;    C₂₋₆alkynyl substituted with one substituent selected from halo,    cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl or R⁷;    —C(═N—O—R⁸)—C₁₋₄alkyl; R⁷ or —X₃—R⁷; in particular-   (b) R³ is cyano; aminocarbonyl; amino; C₁₋₆alkyl; halo; C₁₋₆alkyloxy    wherein C₁₋₆alkyl may optionally be substituted with cyano; NHR³;    NR¹³R¹⁴; —C(═O)—NHR¹³; —C(═O)—NR¹³R¹⁴; —C(═O)—R¹⁵;    —CH═N—NH—C(═O)—R¹⁶; C₁₋₆alkyl substituted with one substituent    selected from halo, cyano, —C(═O)—NR⁹R¹⁰; C₁₋₆alkyl substituted with    hydroxy and a second substituent selected from halo, cyano,    —C(═O)—NR⁹R¹⁰; C₁₋₆alkyloxyC₁₋₆alkyl optionally substituted with one    substituent selected from halo, cyano, —C(═O)—NR⁹R¹⁰; C₂₋₆alkenyl    substituted with one substituent selected from halo, cyano,    —C(═O)—NR⁹R¹⁰; C₂₋₆alkynyl substituted with one substituent selected    from halo, cyano, —C(═O)—NR⁹R¹⁰;-   (c) R³ is halo, cyano, aminocarbonyl, C₁₋₆alkyl optionally    substituted with cyano or aminocarbonyl, C₂₋₆alkenyl optionally    substituted with cyano or aminocarbonyl;-   (d) R³ is halo, cyano, aminocarbonyl, C₁₋₆alkyl substituted with    cyano or aminocarbonyl, or C₂₋₆alkenyl substituted with cyano or    aminocarbonyl;-   (e) R³ is cyano, C₁₋₄alkyl substituted with cyano or C₂₋₄alkenyl    substituted with cyano;-   (f) R³ is C₁₋₄alkyl substituted with cyano or C₂₋₄alkenyl    substituted with cyano;-   (g) R³ is C₂₋₄alkyl substituted with cyano or C₂₋₄alkenyl    substituted with cyano;-   (h) R³ is C₂₋₄alkenyl substituted with cyano;-   (i) R³ is ethenyl substituted with cyano;-   (j) R³ is (E)-2-cyanoethenyl.

Still further subgroups of the compounds of formula (I) are thosecompounds of formula (I), or any subgroup of compounds of formula (I)specified herein, wherein

-   (a) R⁴ is halo; hydroxy; C₁₋₆alkyl optionally substituted with one    substituent selected from halo, cyano or —C(═O)R⁶; C₂₋₆alkenyl    optionally substituted with one substituent selected from halo,    cyano or —C(═O)R⁶; C₂₋₆alkynyl optionally substituted with one    substituent selected from halo, cyano or —C(═O)R⁶; C₃₋₇cycloalkyl;    C₁₋₆alkyloxy; cyano; nitro; polyhaloC₁₋₆alkyl; polyhaloC₁₋₆alkyloxy;    aminocarbonyl; mono- or di(C₁₋₄alkyl)aminocarbonyl;    C₁₋₆alkyloxycarbonyl; C₁₋₆alkylcarbonyl; formyl; amino; mono- or    di(C₁₋₄alkyl)amino or R⁷;-   (b) R⁴ is halo; hydroxy; C₁₋₆alkyl optionally substituted with one    substituent selected from cyano; C₂₋₆alkenyl optionally substituted    with cyano; C₂₋₆alkynyl optionally substituted with cyano;    C₃₋₇cycloalkyl; C₁₋₆alkyloxy; cyano; nitro; trifluoromethyl;    aminocarbonyl; mono- or di(C₁₋₄alkyl)aminocarbonyl;    C₁₋₆alkyloxycarbonyl; C₁₋₆alkylcarbonyl; formyl; amino; mono- or    di(C₁₋₄alkyl)amino or R⁷;-   (c) R⁴ is halo; hydroxy; C₁₋₆alkyl optionally substituted with    cyano; C₂₋₆alkenyl optionally substituted with cyano; C₂₋₆alkynyl    optionally substituted with cyano; C₁₋₆alkyloxy; cyano; nitro;    trifluoromethyl; aminocarbonyl; mono- or di(C₁₋₄alkyl)aminocarbonyl;    C₁₋₆-alkyloxycarbonyl; C₁₋₆alkylcarbonyl; formyl; amino; mono- or    di(C₁₋₄alkyl)amino;-   (d) R⁴ is halo, hydroxy, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,    C₁₋₆alkyloxy, cyano, nitro, amino;-   (e) R⁴ is halo, hydroxy, C₁₋₄alkyl, C₁₋₄alkyloxy, cyano; or (f) R⁴    is halo, C₁₋₄alkyl, C₁₋₄alkyloxy.

Further subgroups of the compounds of formula (I) are those compounds offormula (I), or any subgroup of compounds of formula (I) specifiedherein, wherein

-   (a) R⁵ is a radical of formula —Y-Alk-L, or -Alk′-Y-Alk-L;-   (b) R⁵ is a radical of formula —Y-Alk-L, or -Alk′-Y-Alk-L; wherein L    is Het;-   (c) R⁵ is a radical of formula -Alk′-Y-L;-   (d) R⁵ is a radical of formula -Alk′-Y-L; wherein L is aryl.

Still further subgroups of the compounds of formula (I) are thosecompounds of formula (I), or any subgroup of compounds of formula (I)specified herein, wherein R⁵ is a radical of formula —Y—C_(p)H_(2p)-L or—C_(q)H_(2q)—Y—C_(p)H_(2p)-L; wherein L is aryl or Het; wherein aryl,Het and Y are as specified above or hereinafter; and wherein

-   -   p is 1-6;    -   q is 1-6;        and wherein in particular:

-   (a) Y is O, S, NR¹; —CH═N—O—; (b) Y is O, NR¹; —CH═N—O—; (c) Y is    NR¹ or —CH═N—O—;

-   (b) p is 1-4; or in particular p is 1-2;

-   (c) q is 1-4; or in particular q is 1-2;

Still further subgroups of the compounds of formula (I) are thosecompounds of formula (I), or any subgroup of compounds of formula (I)specified herein, wherein

-   (a) Het is a 5- or 6-membered completely unsaturated ring system    wherein one, two, three or four ring members are hetero atoms each    independently selected from the group consisting of nitrogen, oxygen    and sulfur, and wherein the remaining ring members are carbon atoms;    and, where possible, any nitrogen ring member may optionally be    substituted with C₁₋₆alkyl; which ring system may optionally be    annelated with a benzene ring; and wherein any ring carbon atom,    including any carbon of an optionally annelated benzene ring, may,    each independently, optionally be substituted with a substituent    selected from halo, hydroxy, mercapto, cyano, C₁₋₆alkyl,    hydroxyC₁₋₄alkyl, carboxyC₁₋₄alkyl, C₁₋₄alkyloxy-C₁₋₄alkyl,    cyanoC₁₋₄alkyl, di(C₁₋₄alkyl)aminoC₁₋₄alkyl, Het¹C₁₋₄alkyl,    aryl-C₁₋₄alkyl, polyhaloC₁₋₄alkyl, C₃₋₇cycloalkyl, aryl-C₂₋₄alkenyl,    C₁₋₄alkyloxy, —OCONH₂, polyhaloC₁₋₄alkyloxy, aryloxy, amino, mono-    and di-C₁₋₄alkylamino, C₁₋₄alkylcarbonylamino, formyl,    C₁₋₄alkylcarbonyl, aryl, Het¹;-   (b) Het is a heterocycle selected from pyrrolyl, furanyl, thienyl,    pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,    isothiazolyl, triazolyl, tetrazolyl, thiatriazolyl, thiadiazolyl,    oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,    benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl,    benzothiazolyl, benzotriazolyl, indolyl, benzothiadiazolyl,    benzofurazanyl, benzoxadiazolyl, indazolyl, quinolinyl, said    heterocycle optionally being substituted on its carbon atoms with    one, two or three substituents each independently selected from    halo, hydroxy, mercapto, cyano, C₁₋₆alkyl, hydroxyC₁₋₄alkyl,    carboxyC₁₋₄alkyl, C₁₋₄alkyloxyC₁₋₄alkyl,    C₁₋₄alkyloxycarbonyl-C₁₋₄alkyl, cyanoC₁₋₄alkyl, mono- and    di(C₁₋₄alkyl)aminoC₁₋₄alkyl, Het¹C₁₋₄alkyl, arylC₁₋₄alkyl,    polyhaloC₁₋₄alkyl, C₃₋₇cycloalkyl, arylC₂₋₄alkenyl, C₁₋₄alkyloxy,    —OCONH₂, polyhaloC₁₋₄alkyloxy, aryloxy, amino, mono- and    di-C₁₋₄alkylamino, pyrrolidinyl, piperidinyl, morpholinyl,    piperazinyl, 4-C₁₋₆alkylpiperazinyl, C₁₋₄alkylcarbonylamino, formyl,    C₁₋₄alkylcarbonyl, aryl, C₁₋₄alkyloxycarbonyl, aminocarbonyl, mono-    and diC₁₋₄alkylaminocarbonyl, Het¹;-   (c) Het is a heterocycle selected from pyrrolyl, furanyl, thienyl,    pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,    isothiazolyl, triazolyl, tetrazolyl, thiatriazolyl, thiadiazolyl,    oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,    benzofuranyl, indolyl, benzothiadiazolyl, quinolinyl, said    heterocycle optionally being substituted on its carbon atoms with    one, two or three substituents each independently selected from    halo, hydroxy, cyano, C₁₋₆alkyl, C₁₋₄alkyloxycarbonyl-C₁₋₄alkyl,    amino, mono- and di-C₁₋₄alkylamino, morpholinyl,    C₁₋₄alkylcarbonylamino, aminocarbonyl, mono- and    diC₁₋₄alkylaminocarbonyl, aryl, Het¹;-   (d) Het is a heterocycle selected from pyrrolyl, furanyl, thienyl,    isothiazolyl, thiatriazolyl, thiadiazolyl, oxadiazolyl, pyridyl,    pyrimidinyl, benzofuranyl, quinolinyl, said heterocycle optionally    being substituted on its carbon atoms with one, two or three    substituents each independently selected from halo, hydroxy, cyano,    C₁₋₆alkyl, C₁₋₄alkyloxycarbonyl-C₁₋₄alkyl, amino, mono- and    di-C₁₋₄alkylamino, morpholinyl, C₁₋₄alkylcarbonylamino,    aminocarbonyl, aryl phenyl, Het¹ (the latter in particular being    pyridyl);-   (e) Het is a heterocycle selected from pyrrolyl, furanyl, thienyl,    oxadiazolyl, pyridyl, said heterocycle optionally being substituted    on its carbon atoms with one, two or three substituents each    independently selected from halo, hydroxy, C₁₋₆alkyl, phenyl, Het¹    (the latter in particular being pyridyl).

Still further subgroups of the compounds of formula (I) are thosecompounds of formula (I), or any subgroup of compounds of formula (I)specified herein, wherein

-   (a) Het¹ is pyridyl, thienyl, furanyl, oxazolyl, isoxazolyl,    imidazolyl, pyrazolyl, thiazolyl, thiadiazolyl, oxadiazolyl; which    each may optionally be substituted with one or two C₁₋₄alkyl    radicals;-   (b) Het¹ is pyridyl, thienyl, furanyl; which each may optionally be    substituted with one or two C₁₋₄alkyl radicals; or-   (c) Het¹ is pyridyl, thienyl, furanyl;-   (d) Het¹ is pyridyl.

Still further subgroups of the compounds of formula (I) are thosecompounds of formula (I), or any subgroup of compounds of formula (I)specified herein, wherein

-   (a) Q is hydrogen, C₁₋₆alkyl or —NR⁹R¹⁰; (b) Q is hydrogen or    —NR⁹R¹⁰;-   (c) Q is hydrogen, amino, mono- or di-C₁₋₄alkylamino; or (d) Q is    hydrogen.

Other subgroups of the compounds of formula (I) are those compounds offormula (I), or any subgroup of compounds of formula (I) specifiedherein, wherein

-   (a) R⁶ is C₁₋₄alkyl, amino, mono- or di(C₁₋₄alkyl)amino; in    particular-   (b) R⁶ is C₁₋₄alkyl or amino; or (c) R⁶ is C₁₋₄alkyl.

Still further subgroups of the compounds of formula (I) are thosecompounds of formula (I), or any subgroup of compounds of formula (I)specified herein, wherein

-   (a) R⁷ is a monocyclic or bicyclic, partially saturated or aromatic    carbocycle or a monocyclic or bicyclic, partially saturated or    aromatic heterocycle, wherein each of said carbocyclic or    heterocyclic ring systems may optionally be substituted with one,    two or three substituents each independently selected from halo,    hydroxy, mercapto, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl,    C₁₋₆alkylcarbonyl, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl,    C₁₋₆alkylthio, cyano, nitro, polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy    or aminocarbonyl; in particular-   (b) R⁷ is any of the specific monocyclic or bicyclic, partially    saturated or aromatic carbocycles or monocyclic or bicyclic,    partially saturated or aromatic heterocycles specifically mentioned    in this specification, wherein each of said carbocyclic or    heterocyclic ring systems may optionally be substituted with one,    two or three substituents each independently selected from halo,    hydroxy, mercapto, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl,    C₁₋₆alkylcarbonyl, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl,    C₁₋₆alkylthio, cyano, nitro, polyhalo-C₁₋₆alkyl,    polyhaloC₁₋₆alkyloxy or aminocarbonyl;-   (c) R^(7a) is a monocyclic or bicyclic, partially saturated or    aromatic carbocycle or a monocyclic or bicyclic, partially saturated    or aromatic heterocycle, wherein each of said carbocyclic or    heterocyclic ring systems may optionally be substituted with one,    two or three substituents each independently selected from halo,    hydroxy, mercapto, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl,    C₁₋₆alkylcarbonyl, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl,    C₁₋₆alkylthio, cyano, nitro, polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy    or aminocarbonyl; in particular-   (d) R^(7a) is any of the specific monocyclic or bicyclic, partially    saturated or aromatic carbocycles or monocyclic or bicyclic,    partially saturated or aromatic heterocycles specifically mentioned    in this specification, wherein each of said carbocyclic or    heterocyclic ring systems may optionally be substituted with one,    two or three substituents each independently selected from halo,    hydroxy, mercapto, C₁₋₆alkyl, hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl,    C₁₋₆alkylcarbonyl, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl,    C₁₋₆alkylthio, cyano, nitro, polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy    or aminocarbonyl.

Further subgroups of the compounds of formula (I) are those compounds offormula (I), or any subgroup of compounds of formula (I) specifiedherein, wherein

-   (a) X₃ is —NR¹—, —O— or —S—; (b) X₃ is —NR¹— or —O—; (c) X₃ is —NH—,    —N(C₁₋₄alkyl)-, —O—;-   (d) X₃ is —NH—, —N(CH₃)—, —O—; or (e) X₃ is —NH—, —O—.

Other subgroups of the compounds of formula (I) are those compounds offormula (I), or any subgroup of compounds of formula (I) specifiedherein, wherein

-   (a) R⁸ is hydrogen, C₁₋₄alkyl or arylC₁₋₄alkyl; or (b) R⁸ is    hydrogen or C₁₋₄alkyl.

Other subgroups of the compounds of formula (I) are those compounds offormula (I), or any subgroup of compounds of formula (I) specifiedherein, wherein

-   (a) R⁹ and R¹⁰ each independently are hydrogen; C₁₋₆alkyl;    C₁₋₆alkylcarbonyl; C₁₋₆alkyloxycarbonyl; mono- or    di(C₁₋₆alkyl)aminocarbonyl; —CH(═NR¹¹), wherein each of the    aforementioned C₁₋₆alkyl groups may optionally be substituted with    one or two substituents each independently selected from hydroxy,    C₁₋₆alkyloxy, hydroxyC₁₋₆alkyloxy, carboxyl, C₁₋₆alkyloxycarbonyl,    cyano, amino, mono- or di(C₁₋₁₄alkyl)amino, polyhalomethyl,    polyhalomethyloxy;-   (b) R⁹ and R¹⁰ each independently are hydrogen; C₁₋₆alkyl;    C₁₋₆alkylcarbonyl or C₁₋₆alkyloxycarbonyl;-   (c) R⁹ and R¹⁰ each independently are hydrogen or C₁₋₆alkyl;-   (d) R⁹ and R¹⁰ are hydrogen.

Still other subgroups of the compounds of formula (I) are thosecompounds of formula (I), or any subgroup of compounds of formula (I)specified herein, wherein

-   (a) R¹³ and R¹⁴ each independently are C₁₋₆alkyl optionally    substituted with cyano, C₂₋₆alkenyl optionally substituted with    cyano, C₂₋₆alkynyl optionally substituted with cyano;-   (b) R¹³ and R¹⁴ each independently are hydrogen or C₁₋₆alkyl;-   (c) R¹³ and R¹⁴ are hydrogen.

Still other subgroups of the compounds of formula (I) are thosecompounds of formula (I), or any subgroup of compounds of formula (I)specified herein, wherein R¹⁵ is C₁₋₆alkyl optionally substituted withcyano.

Still other subgroups of the compounds of formula (I) are thosecompounds of formula (I), or any subgroup of compounds of formula (I)specified herein, wherein (a) R¹⁶ is C₁₋₆alkyl optionally substitutedwith cyano or aminocarbonyl; or wherein (b) R¹⁶ is C₁₋₆alkyl optionallysubstituted with cyano.

Still other subgroups of the compounds of formula (I) are thosecompounds of formula (I), or any subgroup of compounds of formula (I)specified herein, wherein

-   (a) aryl is phenyl or phenyl substituted with one, two, three, four    or five substituents each independently selected from halo, hydroxy,    mercapto, C₁₋₆alkyl, hydroxy-C₁₋₆alkyl, aminoC₁₋₆alkyl, mono or    di(C₁₋₆alkyl)aminoC₁₋₆alkyl, C₁₋₆alkylcarbonyl, C₃₋₇cycloalkyl,    C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylthio, cyano, nitro,    polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy, aminocarbonyl, Het¹ or    —X₃-Het¹.-   (b) aryl is phenyl or phenyl substituted with one, two or three    substituents each independently selected from halo, hydroxy,    mercapto, C₁₋₆alkyl, hydroxy-C₁₋₆alkyl, aminoC₁₋₆alkyl, mono or    di(C₁₋₆alkyl)aminoC₁₋₆alkyl, C₁₋₆alkylcarbonyl, C₃₋₇cycloalkyl,    C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylthio, cyano, nitro,    polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy, aminocarbonyl, phenyl,    thienyl or pyridyl;-   (c) aryl is phenyl or phenyl substituted with one, two or three    substituents each independently selected from halo, hydroxy,    mercapto, C₁₋₆alkyl, hydroxy-C₁₋₆alkyl, aminoC₁₋₆alkyl, mono or    di(C₁₋₆alkyl)amino C₁₋₆alkyl, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxy,    C₁₋₆alkyloxycarbonyl, C₁₋₆alylthio, cyano, nitro, trifluoromethyl,    trifluoromethoxy, aminocarbonyl, phenyl;-   (d) aryl is phenyl or phenyl substituted with one, two or three    substituents each independently selected from halo, hydroxy,    C₁₋₆alkyl, hydroxyC₁₋₆alkyl, amino C₁₋₆alkyl, mono or    di(C₁₋₆alkyl)amino C₁₋₆alkyl, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxy,    C₁₋₆alkyloxycarbonyl, cyano, nitro, trifluoromethyl;-   (e) aryl is phenyl or phenyl substituted with one, two or three    substituents each independently selected from halo, hydroxy,    C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, nitro, trifluoromethyl.

Whenever a radical or group occurs more than once in the definitions ofthe compounds of formula (I) each occurrence of said radical or groupindependently can have any of the definitions specified herein.

One embodiment concerns a subgroup of compounds of formula (I) havingthe formula

the N-oxides, the pharmaceutically acceptable addition salts, thequaternary amines or the stereochemically isomeric forms thereof,wherein -b¹=b²-b³=b⁴-, R¹, R², R^(2a), R³, R⁴, R⁵, m, n and X₁ are asdefined hereinabove in the general definition of the compounds offormula (I) or in the various subgroups thereof.

Yet another embodiment concerns a subgroup of compounds of formula (I)having the formula

the N-oxides, the pharmaceutically acceptable addition salts, thequaternary amines or the stereochemically isomeric forms thereof,wherein -a¹=a²-a³=a⁴-, R¹, R², R^(2a), R³, R⁴, R⁵, m, n and X₁ are asdefined hereinabove in the general definition of the compounds offormula (I) or in the various subgroups thereof.

Another embodiment concerns a subgroup of compounds of formula (I)having the formula

the N-oxides, the pharmaceutically acceptable addition salts, thequaternary amines or the stereochemically isomeric forms thereof,wherein R¹, R², R^(2a), R³, R⁴, R⁵, m, n and X₁ are as definedhereinabove in the general definition of the compounds of formula (I) orin the various subgroups thereof.

A further embodiment encompasses a subgroup of compounds of formula (I)having the formula

the N-oxides, the pharmaceutically acceptable addition salts, thequaternary amines or the stereochemically isomeric forms thereof,wherein R¹, R^(2a), R³, R⁴, R⁵ and X₁ are as defined hereinabove in thegeneral definition of the compounds of formula (I) or in the varioussubgroups thereof.

Also an interesting embodiment encompasses a subgroup of compounds offormula (I) having the formula

the N-oxides, the pharmaceutically acceptable addition salts, thequaternary amines or the stereochemically isomeric forms thereof,wherein R¹, R², R^(2a), R³, R⁵ and X₁ are as defined hereinabove in thegeneral definition of the compounds of formula (I) or in the varioussubgroups thereof.

The compounds of formula (I) can be prepared by reacting an intermediateof formula (II) wherein W₁ represents a suitable leaving group, such asfor example halogen, e.g. chloro and the like, with an intermediate offormula (III).

The reaction of the pyrimidine derivative (II) with the amine (III) istypically conducted in the presence of a suitable solvent. Suitablesolvents are for example an alcohol, such as for example ethanol,2-propanol; a dipolar aprotic solvent such as acetonitrile,N,N-dimethylformamide; N,N-dimethylacetamide, 1-methyl-2-pyrrolidinone;an ether such as tetrahydrofuran, 1,4-dioxane, propylene glycolmonomethylether. The reaction may be done under acid conditions whichmay be obtained by adding amounts of a suitable acid, e.g. camphorsulfonic acid, and a suitable solvent, such as for exampletetrahydrofuran or an alcohol, e.g. 2-propanol, or by using acidifiedsolvents, e.g. hydrochloric acid dissolved in an alkanol such as 1- or2-propanol.

The compounds of formula (I) can also be prepared by forming the X₁linkage by either reacting (IV-a) with (V-a) or (IV-b) with (V-b) asoutlined in the following scheme.

In this reaction scheme W₂ represents an appropriate functional group,which combined with the —X₁H group can be transformed into an X₁ link.This procedure is most convenient for the preparation of compounds offormula (I) wherein X₁ is a heteroatom such as —NR¹—, —O—, —S—.

In particular, compounds of formula (I) wherein X₁ represents NR¹, saidcompounds being represented by formula (I-a), can be prepared byreacting an intermediate of formula (IV-c), wherein W₁ is an appropriateleaving group, e.g. chloro or bromo, with an intermediate of formula(V-c). The leaving group W₁ may also be introduced in situ, e.g. byconverting the corresponding hydroxy function into a leaving group forexample by POCl₃. The reaction of (IV-c) with (V-c) preferably isconducted in a suitable solvent in the presence of a base, e.g.triethylamine. Suitable solvents are for example acetonitrile, alcohols,such as for example ethanol, 2-propanol, ethylene glycol, propyleneglycol, polar aprotic solvents such as N,N-dimethyl-formamide;N,N-dimethylacetamide, dimethylsufoxide, 1-methyl-2-pyrrolidinone,[bmim]PF₅; ethers such as 1,4-dioxane, propylene glycol monomethylether.

This conversion is also suited in the instance where X₁ is —O— or —S—.In particular, compounds of formula (I) wherein X₁ represents O, saidcompounds being represented by formula (I-b), can be prepared byreacting an intermediate of formula (VI) wherein W₁ represents asuitable leaving group, such as for example halo, e.g. chloro and thelike, with an intermediate of formula (VII) in the presence of asuitable base, such as for example K₂CO₃ or potassium t-butoxide (KOt-Bu), and a suitable solvent, such as for example acetone ortetrahydrofuran. In a particular execution, intermediate (VII) is firstreacted under stirring at room temperature with a suitable metal hydridein an organic solvent. Subsequently, an intermediate (VI), wherein —W₁is a suitable leaving group, is added.

Compounds of formula (I-b) can also be prepared by reacting anintermediate of formula (IV-b) wherein —X¹H is —OH, said intermediatesbeing represented by (IV-d), with an intermediate of formula (VII) inthe presence of POCl₃, a suitable base, such as for example K₂CO₃ orpotassium t-butoxide (KO t-Bu), and a suitable solvent, such as forexample acetone or tetrahydrofuran.

The thio-compounds (X₁ is —S—) can be obtained in a similar manner andcan conveniently be transferred to the corresponding sulfoxide orsulfone using art-known oxidation procedures.

Compounds of formula (I) wherein X₁ is other than a heteroatom can beprepared by reacting (IV-a) with (V-a) or (IV-b) with (V-b), as outlinedin the above scheme, by selecting the appropriate functional groups —X₁Hand —W₂.

In particular, where X₁ is —C(═O)— a starting material (V-a) or (IV-b)wherein the group —X₁H is a Grignard type of group (—Mg-halo) or lithiumis reacted with a starting material (IV-a) or (V-b) wherein W₂ is anester (—COOalkyl). The latter ester may also be reduced to an alcoholwith e.g. LiAlH₄ and subsequently oxidized with a mild oxidant such asMnO₂ to the corresponding aldehyde which subsequently is reacted withthe appropriate starting material wherein the group —X₁H is a Grignardtype of group (—Mg-halo) or lithium. The compounds wherein —X₁— is—C(═O)— can be converted to the —CHOH— analogs by a suitable reductionreaction e.g. with LiAlH₄.

Where X₁ is —CH₂— this linkage can be introduced by a Grignard reaction,e.g. by reacting a starting material (V-a) or (IV-b) wherein the —X₁Hgroup is —CH₂—Mg-halo with an intermediate (IV-a) or (V-b) wherein W₂ isa halo group. The methylene group can be oxidized to a —C(═O)— group (X₁is —C(═O)—) e.g. with selenium dioxide. The —C(═O)— group in turn can bereduced with a suitable hydride such as LiAlH₄ to a —CHOH— group.

The compounds of formula (I) wherein R is a radical —Y¹—C_(p)H_(2p)-L,wherein Y¹ is O, S or NR¹, said intermediates being represented byformula (I-c) can also be prepared by reacting an intermediate (VIII-a)wherein W₁ represents a suitable leaving group, such as for examplehalogen, e.g. chloro, bromo, with a reagent HY¹—C_(p)H_(2p)-L. Thecompounds (1-c) can also be prepared by reacting an intermediate(VIII-b) with a reagent W₁—C_(p)H_(2p)-L.

The compounds of formula (I-d) which are compounds of formula (I-c)wherein Y¹ is NH can also be prepared by a reductive amination reactionof an intermediate (VIII-a) wherein Y is NH, hereafter represented by(VIII-a-1) with a reagent O═CH—C_(p-1)H_(2p-1)-L. This reaction is donein a suitable solvent in the presence of a reducing agents such ashydrogen in the presence of a noble metal catalyst (e.g. Pd) or an metalhydride, e.g. sodium cyanoborohydride.

The intermediates (VIII-a) can be prepared by halogenating acorresponding starting material (IX). Other leaving groups can beintroduced by replacing the halo group using suitable reagents.

The compounds of formula (I) wherein R⁵ is a radical—C_(q)H_(2q)—Y—C_(p)H_(2p)-L, said compounds being represented byformula (I-e), can also be prepared by reacting an intermediate (X-a)wherein W₁ represents a suitable leaving group, such as for examplehalogen, e.g. chloro, bromo, with a reagent HY—C_(p)H_(2p)-L. Thecompounds (1-e) can also be prepared by reacting an intermediate (X-b)with a reagent W₁—C_(p)H_(2p)-L.

The compounds of formula (I-e), which are compounds of formula (I-d)wherein Y is NH, can also be prepared by a reductive amination reactionof an intermediate (X-c) with a reagent

The intermediates (X-b) or (X-c) can be prepared by reacting acorresponding starting material (X-a) with as suitable nucleophile suchas ammonia, an amine, a metal hydroxide or sulfhydride.

The compounds of formula (I) wherein R⁵ is a radical —Y—C_(p)H_(2p)-L,wherein Y is —CH═N—O—, said compounds being represented by formula(I-f), can be prepared by reacting an intermediate (VIII-a) wherein W₁represents a suitable leaving group, preferably halogen, e.g. chloro,bromo, with carbon monoxide in the presence of a suitable catalyst suchas dichlorobis(triphenylphosphine)palladium(II). The resulting aldehyde(VIII-c) is reacted with a reagent W₂—C_(p)H_(2p)-L, wherein W₂represents a suitable leaving group, preferably halogen, e.g. chloro,bromo, yielding the desired compounds of formula (I-f).

The compounds of formula (I) may further be prepared by convertingcompounds of formula (I) into each other according to art-known grouptransformation reactions.

The compounds of formula (I) may be converted to the correspondingN-oxide forms following art-known procedures for converting a tertiarynitrogen into its N-oxide form. Said N-oxidation reaction may generallybe carried out by reacting the starting material of formula (I) with anappropriate organic or inorganic peroxide. Appropriate inorganicperoxides comprise, for example, hydrogen peroxide, alkali metal orearth alkaline metal peroxides, e.g. sodium peroxide, potassiumperoxide; appropriate organic peroxides may comprise peroxy acids suchas, for example, benzenecarboperoxoic acid or halo substitutedbenzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid,peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g.tert.butyl hydro-peroxide. Suitable solvents are, for example, water,lower alcohols, e.g. ethanol and the like, hydrocarbons, e.g. toluene,ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g.dichloromethane, and mixtures of such solvents.

Compounds of formula (I) wherein R¹, R^(2a), R³ or R⁴ is C₂₋₆alkenylsubstituted with aminocarbonyl, can be converted into a compound offormula (I) wherein R², R^(2a), R³ or R⁴ is C₂₋₆alkenyl substituted withcyano by reaction with POCl₃.

Compounds of formula (I) wherein m is zero, can be converted into acompound of formula (I) wherein m is other than zero and R⁴ representshalo, by reaction with a suitable halo-introducing agent, such as forexample N-chlorosuccinimide or N-borosuccinimide, or a combinationthereof, in the presence of a suitable solvent, such as for exampleacetic acid.

Compounds of formula (I) wherein R³ represents halo, may be convertedinto a compound of formula (I) wherein R³ represents C₂₋₆alkenylsubstituted with one or more substituents each independently selectedfrom halo, cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl or R⁷, byreaction with the corresponding C₂₋₆alkene substituted with one or moresubstituents each independently selected from halo, cyano, NR⁹R¹⁰,—C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl or R⁷ in the presence of a suitablebase, such as for example N,N-diethyl-ethanamine, a suitable catalyst,such as for example palladium acetate in the presence oftriphenylphosphine, and a suitable solvent, such as for exampleN,N-dimethylformamide.

Compounds of formula (I) wherein R^(2a) represents halo, may beconverted into a compound of formula (I) wherein R^(2a) representsC₂₋₆alkenyl substituted with one or more substituents each independentlyselected from halo, cyano, NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl orR⁷, by reaction with the corresponding C₂₋₆alkene substituted with oneor more substituents each independently selected from halo, cyano,NR⁹R¹⁰, —C(═O)—NR⁹R¹⁰, —C(═O)—C₁₋₆alkyl or R⁷ in the presence of asuitable base, such as for example N,N-diethyl-ethanamine, a suitablecatalyst, such as for example palladium acetate in the presence oftriphenylphosphine, and a suitable solvent, such as for exampleN,N-dimethylformamide.

Compounds of formula (I) wherein R¹ represents C₁₋₆alkyloxycarbonyl, canbe converted into a compound of formula (I) wherein R¹ representshydrogen, by reaction with a suitable base, such as for example sodiumhydroxide or methoxide. Where R¹ is t.butyloxycarbonyl, thecorresponding compounds wherein R¹ is hydrogen can be made by treatmentwith trifluoroacetic acid.

Some of the compounds of formula (I) and some of the intermediates inthe present invention may contain an asymmetric carbon atom. Purestereochemically isomeric forms of said compounds and said intermediatescan be obtained by the application of art-known procedures. For example,diastereoisomers can be separated by physical methods such as selectivecrystallization or chromatographic techniques, e.g. counter currentdistribution, liquid chromatography and the like methods. Enantiomerscan be obtained from racemic mixtures by first converting said racemicmixtures with suitable resolving agents such as, for example, chiralacids, to mixtures of diastereomeric salts or compounds; then physicallyseparating said mixtures of diastereomeric salts or compounds by, forexample, selective crystallization or chromatographic techniques, e.g.liquid chromatography and the like methods; and finally converting saidseparated diastereomeric salts or compounds into the correspondingenantiomers. Pure stereochemically isomeric forms may also be obtainedfrom the pure stereochemically isomeric forms of the appropriateintermediates and starting materials, provided that the interveningreactions occur stereospecifically.

An alternative manner of separating the enantiomeric forms of thecompounds of formula (I) and intermediates involves liquidchromatography, in particular liquid chromatography using a chiralstationary phase.

Some of the intermediates and starting materials are known compounds andmay be commercially available or may be prepared according to art-knownprocedures.

Intermediates of formula (II) can be prepared by reacting anintermediate of formula (XI) wherein W₁ is defined as hereinabove, withan intermediate of formula (XII) in the presence of a suitable solvent,such as for example tetrahydrofuran, and optionally in the presence of asuitable base, such as for example Na₂CO₃.

Intermediates of formula (XI) can be prepared in accordance withart-known procedures.

Intermediates of formula (III) wherein R¹ is hydrogen, saidintermediates being represented by formula (III-a), or intermediates(V-a-1), which are intermediates (V-a) wherein —X¹H is —NH₂, can beprepared by reacting an intermediate of formula (XIII) or (XIV) with asuitable reducing agent, such as Fe, in the presence of NH₄Cl and asuitable solvent, such as for example tetrahydrofuran, H₂O and analcohol, e.g. methanol and the like.

Intermediates of formula (III-a) or (V-a-1) wherein R^(2a) respectivelyR³ represents C₂₋₆alkyl substituted with cyano, said intermediates beingrepresented by formula (III-a-1) and (V-a-2), can be prepared byreacting an intermediate of formula (XIII-a) respectively (XIV-a) withPd/C in the presence of a suitable solvent, such as for example analcohol, e.g. ethanol and the like.

Intermediates of formula (III), (V-a) or (VII) wherein R^(2a)respectively R³ is halo, said intermediates being represented by formula(III-b), (V-b) and (VII-a), may be converted into an intermediate offormula (III) respectively (V) or (VII) wherein R^(2a) respectively R³is C₂₋₆alkenyl substituted with C(═O)NR⁹R¹⁰, said intermediates beingrepresented by formula (III-c), (V-c) and (VII-b) by reaction with anintermediate of formula (XIII) in the presence of Pd(OAc)₂, P(o-Tol)₃, asuitable base, such as for example N,N-diethylethanamine, and a suitablesolvent, such as for example CH₃—CN.

Intermediates of formula (III-c), (V-c) and (VII-b) can also be preparedby reacting an intermediate of formula (II-f), (V-f) and (VII-c) withH—NR⁹R¹⁰ in the presence of oxalyl chloride and in the presence of asuitable solvent, such as for example N,N-dimethylformamide, CH₂Cl₂ andtetrahydrofuran.

Intermediates of formula (III-d), (V-d) and (VII-c) can be prepared byreacting an intermediate of formula (III-b), (V-b) and (VII-a), withH—C₂₋₆alkenyl-C(═O)—OH in the presence of Pd(OAc)₂, P(o-Tol)₃, asuitable base, such as for example N,N-diethylethanamine, and a suitablesolvent, such as for example CH₃—CN.

Intermediates of formula (III-b), (V-b) and (VII-a), may also beconverted into an intermediate of formula (III) respectively (V) or(VII) wherein R²¹ respectively R³ is C₂₋₆alkenyl substituted with CN,said intermediates being represented by formula (III-e), (V-e) and(VII-d) by reaction with H—C₂₋₆alkenyl-CN in the presence of Pd(OAc)₂,P(o-Tol)₃, a suitable base, such as for example N,N-diethylethanamine,and a suitable solvent, such as for example CH₃—CN.

Intermediates of formula (XV) can be prepared by reacting anintermediate of formula (XVI) wherein W₃ represents a suitable leavinggroup, such as for example halogen, e.g. chloro, with H—NR⁹R¹⁰ (XVII) inthe presence of a suitable solvent, such as for example diethylether andtetrahydrofuran.

Intermediates of formula (XIII) or (XIV) wherein R^(2a) respectively R³represents cyanovinyl, said intermediates being represented by formula(XIII-b) and (XIV-b), can be prepared by reacting an intermediate offormula (XVIII) respectively (XIX) with diethylcyanomethylphosphonate inthe presence of a suitable base, such as for example NaOCH₃, and asuitable solvent, such as for example tetrahydrofuran.

Intermediates of formula (XIII) or (XIV) wherein R^(2a) respectively R³represents —C(CH₃)═CH—CN, said intermediates being represented byformula (XIII-c) and (XIII-c), can be prepared by reacting anintermediate of formula (XX) respectively (XXI) withdiethylcyanomethylphosphonate in the presence of a suitable base, suchas for example NaOCH₃, and a suitable solvent, such as for exampletetrahydrofuran.

Intermediates of formula (XVIII) and (XIX) can be prepared by reactingan intermediate of formula (XXII) respectively (XXIII) with a suitableoxidizing agent, such as for example MnO₂, in the presence of a suitablesolvent, such as for example acetone.

Intermediates of formula (XXII) and (XXIII) can be prepared by reactingan intermediate of formula (XXIV) respectively (XXV) with NaBH₄ in thepresence of ethylchloroformate, a suitable base, such as for exampleN,N-diethylethanamine, and a suitable solvent, such as for exampletetrahydrofuran.

Intermediates of formula (XIII) and (XIV) wherein R^(2a) respectively R³represent hydroxy, said intermediates being represented by formula(XIII-d) respectively (XIV-d), can be converted into an intermediate offormula (XIII) respectively (XIV) wherein R^(2a) respectively R³represent C₁₋₆alkyloxy wherein the C₁₋₆alkyl may optionally besubstituted with cyano, said R^(2a) respectively R³ being represented byP and said intermediates being represented by formula (XIII-e)respectively (XIV-e), by reaction with an intermediate of formula (XXV)wherein W₄ represents a suitable leaving group, such as for examplehalogen, e.g. chloro and the like, in the presence of NaI, a suitablebase, such as for example K₂CO₃, and a suitable solvent, such as forexample acetone.

Intermediates of formula (XIII) and (XIV) can be prepared by reacting anintermediate of formula (XXVI) respectively (XXVII) with NaNO₃ in thepresence of CH₃SO₃H.

The intermediates of formula (IV-d) can be prepared as follows

Intermediates of formula (XXX) can be converted into intermediates offormula (IV-e) which are intermediates of formula (IV-d) wherein R⁵represents bromo by reaction with Br₂ in the presence of a suitablebase, such as for example N,N-diethylethanamine, and a suitable solvent,such as for example dimethylsulfoxide.

Intermediates of formula (IV-e) can be converted into intermediates offormula (VI) wherein R⁵ and W₂ represent chloro, said intermediate beingrepresented by formula (VI-a), by reaction with POCl₃.

The compounds of formula (I) show antiretroviral properties (reversetranscriptase inhibiting properties), in particular against HumanImmunodeficiency Virus (HIV), which is the aetiological agent ofAcquired Immune Deficiency Syndrome (AIDS) in humans. The HIV viruspreferentially infects human T-4 cells and destroys them or changestheir normal function, particularly the coordination of the immunesystem. As a result, an infected patient has an ever decreasing numberof T-4 cells, which moreover behave abnormally. Hence, the immunologicaldefense system is unable to combat infections and neoplasms and the HIVinfected subject usually dies by opportunistic infections such aspneumonia, or by cancers. Other conditions associated with HIV infectioninclude thrombocytopaenia, Kaposi's sarcoma and infection of the centralnervous system characterized by progressive demyelination, resulting indementia and symptoms such as, progressive dysarthria, ataxia anddisorientation. HIV infection further has also been associated withperipheral neuropathy, progressive generalized lymphadenopathy (PGL) andAIDS-related complex (ARC).

The present compounds also show activity against (multi) drug resistantHIV strains, in particular (multi) drug resistant HIV-1 strains, more inparticular the present compounds show activity against HIV strains,especially HIV-1 strains, that have acquired resistance to one or moreart-known non-nucleoside reverse transcriptase inhibitors. Art-knownnon-nucleoside reverse transcriptase inhibitors are those non-nucleosidereverse transcriptase inhibitors other than the present compounds andknown to the person skilled in the art, in particular commercialnon-nucleoside reverse transcriptase inhibitors. The present compoundsalso have little or no binding affinity to human α-1 acid glycoprotein;human α-1 acid glycoprotein does not or only weakly affect the anti HIVactivity of the present compounds.

Due to their antiretroviral properties, particularly their anti-HIVproperties, especially their anti-HIV-1-activity, the compounds offormula (I), their N-oxides, pharmaceutically acceptable addition salts,quaternary amines and stereochemically isomeric forms thereof, areuseful in the treatment of individuals infected by HIV and for theprophylaxis of these infections. In general, the compounds of thepresent invention may be useful in the treatment of warm-blooded animalsinfected with viruses whose existence is mediated by, or depends upon,the enzyme reverse transcriptase. Conditions which may be prevented ortreated with the compounds of the present invention, especiallyconditions associated with HIV and other pathogenic retroviruses,include AIDS, AIDS-related complex (ARC), progressive generalizedlymphadenopathy (PGL), as well as chronic Central Nervous Systemdiseases caused by retroviruses, such as, for example HIV mediateddementia and multiple sclerosis.

The compounds of the present invention or any subgroup thereof maytherefore be used as medicines against above-mentioned conditions. Saiduse as a medicine or method of treatment comprises the administration toHIV-infected subjects of an amount effective to combat the conditionsassociated with HIV and other pathogenic retroviruses, especially HIV-1.In particular, the compounds of formula (I) may be used in themanufacture of a medicament for the treatment or the prevention of HIVinfections.

In view of the utility of the compounds of formula (I), there isprovided a method of treating warm-blooded animals, including humans,suffering from or a method of preventing warm-blooded animals, includinghumans, to suffer from viral infections, especially HIV infections. Saidmethod comprises the administration, preferably oral administration, ofan effective amount of a compound of formula (I), a N-oxide form, apharmaceutically acceptable addition salt, a quaternary amine or apossible stereoisomeric form thereof, to warm-blooded animals, includinghumans.

The present invention also provides compositions for treating viralinfections comprising a therapeutically effective amount of a compoundof formula (I) and a pharmaceutically acceptable carrier or diluent.

The compounds of the present invention or any subgroup thereof may beformulated into various pharmaceutical forms for administrationpurposes. As appropriate compositions there may be cited allcompositions usually employed for systemically administering drugs. Toprepare the pharmaceutical compositions of this invention, an effectiveamount of the particular compound, optionally in addition salt form, asthe active ingredient is combined in intimate admixture with apharmaceutically acceptable carrier, which carrier may take a widevariety of forms depending on the form of preparation desired foradministration. These pharmaceutical compositions are desirable inunitary dosage form suitable, particularly, for administration orally,rectally, percutaneously, or by parenteral injection. For example, inpreparing the compositions in oral dosage form, any of the usualpharmaceutical media may be employed such as, for example, water,glycols, oils, alcohols and the like in the case of oral liquidpreparations such as suspensions, syrups, elixirs, emulsions andsolutions; or solid carriers such as starches, sugars, kaolin, diluents,lubricants, binders, disintegrating agents and the like in the case ofpowders, pills, capsules, and tablets. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit forms, in which case solid pharmaceutical carriers areobviously employed. For parenteral compositions, the carrier willusually comprise sterile water, at least in large part, though otheringredients, for example, to aid solubility, may be included. Injectablesolutions, for example, may be prepared in which the carrier comprisessaline solution, glucose solution or a mixture of saline and glucosesolution. Injectable suspensions may also be prepared in which caseappropriate liquid carriers, suspending agents and the like may beemployed. Also included are solid form preparations which are intendedto be converted, shortly before use, to liquid form preparations. In thecompositions suitable for percutaneous administration, the carrieroptionally comprises a penetration enhancing agent and/or a suitablewetting agent, optionally combined with suitable additives of any naturein minor proportions, which additives do not introduce a significantdeleterious effect on the skin. Said additives may facilitate theadministration to the skin and/or may be helpful for preparing thedesired compositions. These compositions may be administered in variousways, e.g., as a transdermal patch, as a spot-on, as an ointment. Thecompounds of the present invention may also be administered viainhalation or insufflation by means of methods and formulations employedin the art for administration via this way. Thus, in general thecompounds of the present invention may be administered to the lungs inthe form of a solution, a suspension or a dry powder. Any systemdeveloped for the delivery of solutions, suspensions or dry powders viaoral or nasal inhalation or insufflation are suitable for theadministration of the present compounds.

To aid solubility of the compounds of formula (I), suitable ingredients,e.g. cyclodextrins, may be included in the compositions. Appropriatecyclodextrins are α-, β-, γ-cyclodextrins or ethers and mixed ethersthereof wherein one or more of the hydroxy groups of the anhydroglucoseunits of the cyclodextrin are substituted with C₁₋₆alkyl, particularlymethyl, ethyl or isopropyl, e.g. randomly methylated β-CD;hydroxyC₁₋₆alkyl, particularly hydroxyethyl, hydroxy-propyl orhydroxybutyl; carboxyC₁₋₆alkyl, particularly carboxymethyl orcarboxy-ethyl; C₁₋₆alkylcarbonyl, particularly acetyl. Especiallynoteworthy as complexants and/or solubilizers are β-CD, randomlymethylated β-CD, 2,6-dimethyl-β-CD, 2-hydroxyethyl-β-CD,2-hydroxyethyl-β-CD, 2-hydroxypropyl-β-CD and(2-carboxymethoxy)propyl-β-CD, and in particular 2-hydroxypropyl-β-CD(2-HP-β-CD).

The term mixed ether denotes cyclodextrin derivatives wherein at leasttwo cyclodextrin hydroxy groups are etherified with different groupssuch as, for example, hydroxy-propyl and hydroxyethyl.

The average molar substitution (M.S.) is used as a measure of theaverage number of moles of alkoxy units per mole of anhydroglucose. Theaverage substitution degree (D.S.) refers to the average number ofsubstituted hydroxyls per anhydroglucose unit. The M.S. and D.S. valuecan be determined by various analytical techniques such as nuclearmagnetic resonance (NMR), mass spectrometry (MS) and infraredspectroscopy (IR). Depending on the technique used, slightly differentvalues may be obtained for one given cyclodextrin derivative.Preferably, as measured by mass spectrometry, the M.S. ranges from 0.125to 10 and the D.S. ranges from 0.125 to 3.

Other suitable compositions for oral or rectal administration compriseparticles consisting of a solid dispersion comprising a compound offormula (I) and one or more appropriate pharmaceutically acceptablewater-soluble polymers.

The term “a solid dispersion” used hereinafter defines a system in asolid state (as opposed to a liquid or gaseous state) comprising atleast two components, in casu the compound of formula (I) and thewater-soluble polymer, wherein one component is dispersed more or lessevenly throughout the other component or components (in case additionalpharmaceutically acceptable formulating agents, generally known in theart, are included, such as plasticizers, preservatives and the like).When said dispersion of the components is such that the system ischemically and physically uniform or homogenous throughout or consistsof one phase as defined in thermo-dynamics, such a solid dispersion willbe called “a solid solution”. Solid solutions are preferred physicalsystems because the components therein are usually readily bioavailableto the organisms to which they are administered. This advantage canprobably be explained by the ease with which said solid solutions canform liquid solutions when contacted with a liquid medium such as thegastrointestinal juices. The ease of dissolution may be attributed atleast in part to the fact that the energy required for dissolution ofthe components from a solid solution is less than that required for thedissolution of components from a crystalline or microcrystalline solidphase.

The term “a solid dispersion” also comprises dispersions, which are lesshomogenous throughout than solid solutions. Such dispersions are notchemically and physically uniform throughout or comprise more than onephase. For example, the term “a solid dispersion” also relates to asystem having domains or small regions wherein amorphous,microcrystalline or crystalline compound of formula (I), or amorphous,microcrystalline or crystalline water-soluble polymer, or both, aredispersed more or less evenly in another phase comprising water-solublepolymer, or compound of formula (I), or a solid solution comprisingcompound of formula (I) and water-soluble polymer. Said domains areregions within the solid dispersion distinctively marked by somephysical feature, small in size, and evenly and randomly distributedthroughout the solid dispersion.

Various techniques exist for preparing solid dispersions includingmelt-extrusion, spray-drying and solution-evaporation.

The solution-evaporation process comprises the following steps

-   a) dissolving the compound of formula (I) and the water-soluble    polymer in an appropriate solvent, optionally at elevated    temperatures;-   b) heating the solution resulting under point a), optionally under    vacuum, until the solvent is evaporated. The solution may also be    poured onto a large surface so as to form a thin film, and    evaporating the solvent therefrom.

In the spray-drying technique, the two components are also dissolved inan appropriate solvent and the resulting solution is then sprayedthrough the nozzle of a spray dryer followed by evaporating the solventfrom the resulting droplets at elevated temperatures.

The preferred technique for preparing solid dispersions is themelt-extrusion process comprising the following steps:

-   -   a) mixing a compound of formula (I) and an appropriate        water-soluble polymer,    -   b) optionally blending additives with the thus obtained mixture,    -   c) heating and compounding the thus obtained blend until one        obtains a homogenous melt,    -   d) forcing the thus obtained melt through one or more nozzles;        and    -   e) cooling the melt until it solidifies.

The terms “melt” and “melting” should be interpreted broadly. Theseterms not only mean the alteration from a solid state to a liquid state,but can also refer to a transition to a glassy state or a rubbery state,and in which it is possible for one component of the mixture to getembedded more or less homogeneously into the other. In particular cases,one component will melt and the other component(s) will dissolve in themelt thus forming a solution, which upon cooling may form a solidsolution having advantageous dissolution properties.

After preparing the solid dispersions as described hereinabove, theobtained products can be optionally milled and sieved.

The solid dispersion product may be milled or ground to particles havinga particle size of less than 600 μm, preferably less than 400 μm andmost preferably less than 125 μm.

The particles prepared as described hereinabove can then be formulatedby conventional techniques into pharmaceutical dosage forms such astablets and capsules.

It will be appreciated that a person of skill in the art will be able tooptimize the parameters of the solid dispersion preparation techniquesdescribed above, such as the most appropriate solvent, the workingtemperature, the kind of apparatus being used, the rate of spray-drying,the throughput rate in the melt-extruder.

The water-soluble polymers in the particles are polymers that have anapparent viscosity, when dissolved at 20° C. in an aqueous solution at2% (w/v), of 1 to 5000 mPa.s more preferably of 1 to 700 mPa.s, and mostpreferred of 1 to 100 mPa.s. For example, suitable water-solublepolymers include alkylcelluloses, hydroxyalkylcelluloses, hydroxyalkylalkylcelluloses, carboxyalkylcelluloses, alkali metal salts ofcarboxyalkylcelluloses, carboxyalkylalkylcelluloses,carboxyalkylcellulose esters, starches, pectines, chitin derivates, di-,oligo- and polysaccharides such as trehalose, alginic acid or alkalimetal and ammonium salts thereof, carrageenans, galactomannans,tragacanth, agar-agar, gummi arabicum, guar gummi and xanthan gummi,polyacrylic acids and the salts thereof, polymethacrylic acids and thesalts thereof, methacrylate copolymers, polyvinylalcohol,polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinylacetate, combinations of polyvinylalcohol and polyvinylpyrrolidone,polyalkylene oxides and copolymers of ethylene oxide and propyleneoxide. Preferred water-soluble polymers are hydroxypropylmethylcelluloses. Also one or more cyclodextrins can be used aswater-soluble polymer in the preparation of the above-mentionedparticles as is disclosed in WO 97/18839. Said cyclodextrins include thepharmaceutically acceptable unsubstituted and substituted cyclodextrinsknown in the art, more particularly α, β or γ cyclodextrins or thepharmaceutically acceptable derivatives thereof.

Substituted cyclodextrins which can be used to prepare the abovedescribed particles include polyethers described in U.S. Pat. No.3,459,731. Further substituted cyclodextrins are ethers wherein thehydrogen of one or more cyclodextrin hydroxy groups is replaced byC₁₋₆alkyl, hydroxy C₁₋₆alkyl, carboxy-C₁₋₆alkyl orC₁₋₆alkyloxycarbonyl-C₁₋₆alkyl or mixed ethers thereof. In particularsuch substituted cyclodextrins are ethers wherein the hydrogen of one ormore cyclodextrin hydroxy groups is replaced by C₁₋₃alkyl,hydroxyC₂₋₄alkyl or carboxyC₁₋₂alkyl or more in particular by methyl,ethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, carboxy-methyl orcarboxyethyl.

Of particular utility are the β-cyclodextrin ethers, e.g.dimethyl-β-cyclodextrin as described in Drugs of the Future, Vol. 9, No.8, p. 577-578 by M. Nogradi (1984) and polyethers, e.g. hydroxypropylβ-cyclodextrin and hydroxyethyl β-cyclodextrin, being examples. Such analkyl ether may be a methyl ether with a degree of substitution of about0.125 to 3, e.g. about 0.3 to 2. Such a hydroxypropyl cyclodextrin mayfor example be formed from the reaction between β-cyclodextrin anpropylene oxide and may have a MS value of about 0.125 to 10, e.g. about0.3 to 3.

Another type of substituted cyclodextrins is sulfobutylcyclodextrines.

The ratio of the compound of formula (I) over the water soluble polymermay vary widely. For example ratios of 1/100 to 100/1 may be applied.Interesting ratios of the compound of formula (I) over cyclodextrinrange from about 1/10 to 10/1. More interesting ratios range from about1/5 to 5/1.

It may further be convenient to formulate the compounds of formula (I)in the form of nanoparticles which have a surface modifier adsorbed onthe surface thereof in an amount sufficient to maintain an effectiveaverage particle size of less than 1000 nm. Useful surface modifiers arebelieved to include those which physically adhere to the surface of thecompound of formula (I) but do not chemically bond to said compound.

Suitable surface modifiers can preferably be selected from known organicand inorganic pharmaceutical excipients. Such excipients include variouspolymers, low molecular weight oligomers, natural products andsurfactants. Preferred surface modifiers include nonionic and anionicsurfactants.

Yet another interesting way of formulating the compounds of formula (I)involves a pharmaceutical composition whereby the compounds of formula(I) are incorporated in hydrophilic polymers and applying this mixtureas a coat film over many small beads, thus yielding a composition whichcan conveniently be manufactured and which is suitable for preparingpharmaceutical dosage forms for oral administration.

Said beads comprise a central, rounded or spherical core, a coating filmof a hydrophilic polymer and a compound of formula (I) and optionally aseal-coating layer.

Materials suitable for use as cores in the beads are manifold, providedthat said materials are pharmaceutically acceptable and have appropriatedimensions and firmness. Examples of such materials are polymers,inorganic substances, organic substances, and saccharides andderivatives thereof.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in unit dosage form for ease ofadministration and uniformity of dosage. Unit dosage form as used hereinrefers to physically discrete units suitable as unitary dosages, eachunit containing a predetermined quantity of active ingredient calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. Examples of such unit dosage forms aretablets (including scored or coated tablets), capsules, pills, powderpackets, wafers, suppositories, injectable solutions or suspensions andthe like, and segregated multiples thereof.

Those of skill in the treatment of HIV-infection could determine theeffective daily amount from the test results presented here. In generalit is contemplated that an effective daily amount would be from 0.01mg/kg to 50 mg/kg body weight, more preferably from 0.1 mg/kg to 10mg/kg body weight. It may be appropriate to administer the required doseas two, three, four or more sub-doses at appropriate intervalsthroughout the day. Said sub-doses may be formulated as unit dosageforms, for example, containing 1 to 1000 mg, and in particular 5 to 200mg of active ingredient per unit dosage form.

The exact dosage and frequency of administration depends on theparticular compound of formula (I) used, the particular condition beingtreated, the severity of the condition being treated, the age, weightand general physical condition of the particular patient as well asother medication the individual may be taking, as is well known to thoseskilled in the art. Furthermore, it is evident that said effective dailyamount may be lowered or increased depending on the response of thetreated subject and/or depending on the evaluation of the physicianprescribing the compounds of the instant invention. The effective dailyamount ranges mentioned hereinabove are therefore only guidelines andare not intended to limit the scope or use of the invention to anyextent.

The present compounds of formula (I) can be used alone or in combinationwith other therapeutic agents, such as anti-virals, antibiotics,immunomodulators or vaccines for the treatment of viral infections. Theymay also be used alone or in combination with other prophylacetic agentsfor the prevention of viral infections. The present compounds may beused in vaccines and methods for protecting individuals against viralinfections over an extended period of time. The compounds may beemployed in such vaccines either alone or together with other compoundsof this invention or together with other anti-viral agents in a mannerconsistent with the conventional utilization of reverse transcriptaseinhibitors in vaccines. Thus, the present compounds may be combined withpharmaceutically acceptable adjuvants conventionally employed invaccines and administered in prophylactically effective amounts toprotect individuals over an extended period of time against HIVinfection.

Also, the combination of one or more additional antiretroviral compoundsand a compound of formula (I) can be used as a medicine. Thus, thepresent invention also relates to a product containing (a) a compound offormula (I), and (b) one or more additional antiretroviral compounds, asa combined preparation for simultaneous, separate or sequential use inanti-HIV treatment. The different drugs may be combined in a singlepreparation together with pharmaceutically acceptable carriers. Saidother antiretroviral compounds may be any known antiretroviral compoundssuch as suramine, pentamidine, thymopentin, castanospermine, dextran(dextran sulfate), foscamet-sodium (trisodium phosphono formate);nucleoside reverse transcriptase inhibitors (NRTIs), e.g. zidovudine(AZT), didanosine (ddI), zalcitabine (ddC), lamivudine (3TC), stavudine(d4T), emtricitabine (FTC), abacavir (ABC), D-D4FC (Reverset™),alovudine (MIV-310), amdoxovir (DAPD), elvucitabine (ACH-126,443), andthe like; non-nucleoside reverse transcriptase inhibitors (NNRTIs) suchas delarvidine (DLV), efavirenz (EFV), nevirapine (NVP), capravirine(CPV), calanolide A, TMC120, etravirine (TMC125), TMC278, BMS-561390,DPC-083 and the like; nucleotide reverse transcriptase inhibitors(NtRTIs), e.g. tenofovir (TDF) and tenofovir disoproxil fumarate, andthe like; compounds of the TIBO(tetrahydroimidazo-[4,5,1-jk][1,4]-benzodiazepine-2(1H)-one andthione)-type e.g.(S)-8-chloro-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo-[4,5,1-jk][1,4]benzodiazepine-2(1H)-thione;compounds of the α-APA (α-anilino phenyl acetamide) type e.g.α-[(2-nitrophenyl)amino]-2,6-dichlorobenzene-acetamide and the like;inhibitors of trans-activating proteins, such as TAT-inhibitors, e.g.RO-5-3335; REV inhibitors; protease inhibitors e.g. ritonavir (RTV),saquinavir (SQV), lopinavir (ABT-378 or LPV), indinavir (IDV),amprenavir (VX-478), TMC-126, BMS-232632, VX-175, DMP-323, DMP-450(Mozenavir), nelfinavir (AG-1343), atazanavir (BMS 232,632), palinavir,TMC-114, RO033-4649, fosamprenavir (GW433908 or VX-175), P-1946, BMS186,318, SC-55389a, L-756,423, tipranavir (PNU-140690), BILA 1096 BS,U-140690, and the like; entry inhibitors which comprise fusioninhibitors (e.g. T-20, T-1249), attachment inhibitors and co-receptorinhibitors; the latter comprise the CCR5 antagonists and CXR4antagonists (e.g. AMD-3100); examples of entry inhibitors areenfuvirtide (ENF), GSK-873,140, PRO-542, SCH-417,690, TNX-355, maraviroc(UK-427,857); a maturation inhibitor for example is PA-457 (PanacosPharmaceuticals); inhibitors of the viral integrase; ribonucleotidereductase inhibitors (cellular inhibitors), e.g. hydroxyurea and thelike.

By administering the compounds of the present invention with otheranti-viral agents which target different events in the viral life cycle,the therapeutic effect of these compounds can be potentiated.Combination therapies as described above exert a synergistic effect ininhibiting HIV replication because each component of the combinationacts on a different site of HIV replication. The use of suchcombinations may reduce the dosage of a given conventionalanti-retroviral agent which would be required for a desired therapeuticor prophylacetic effect as compared to when that agent is administeredas a monotherapy. These combinations may reduce or eliminate the sideeffects of conventional single anti-retroviral therapy while notinterfering with the anti-viral activity of the agents. Thesecombinations reduce potential of resistance to single agent therapies,while minimizing any associated toxicity. These combinations may alsoincrease the efficacy of the conventional agent without increasing theassociated toxicity.

The compounds of the present invention may also be administered incombination with immunomodulating agents, e.g. levamisole, bropirimine,anti-human alpha interferon antibody, interferon alpha, interleukin 2,methionine enkephalin, diethyldithiocarbamate, tumor necrosis factor,naltrexone and the like; antibiotics, e.g. pentamidine isethiorate andthe like; cholinergic agents, e.g. tacrine, rivastigmine, donepezil,galantamine and the like; NMDA channel blockers, e.g. memantine toprevent or combat infection and diseases or symptoms of diseasesassociated with HIV infections, such as AIDS and ARC, e.g. dementia. Acompound of formula (I) can also be combined with another compound offormula (I).

Although the present invention focuses on the use of the presentcompounds for preventing or treating HIV infections, the presentcompounds may also be used as inhibitory agents for other viruses whichdepend on similar reverse transcriptases for obligatory events in theirlife cycle.

The following examples are intended to illustrate the present invention.

EXAMPLES

Hereinafter, “DMSO” is defined as dimethylsulfoxide, “TFA” is defined astrifluoroacetic acid, “DMF” is defined as N,N-dimethylformamide and“THF” is defined as tetrahydrofuran.

A. Preparation of the Intermediate Compounds

Example A1 Preparation of Intermediate 2

N-bromosuccinimide (0.0393 mol) was added portion wise at roomtemperature to Intermediate 1, the preparation of which has beendescribed in WO-03/016306 (0.0327 mol) in CH₃CN (100 ml). The mixturewas stirred at room temperature for 4 hours. The precipitate wasfiltered off, washed with CH₃CN and dried yielding 10.08 g of thedesired end product. The filtrate was evaporated and purified by columnchromatography (eluent: CH₂Cl₂ 100; 35-70 μm). The pure fractions werecollected, the solvent was evaporated and the residue was crystallizedfrom CH₃CN. Yielding: 2.4 g of Intermediate 2. The two fractions werecollected. Yielding: 12.48 g of Intermediate 2 (86%, meltingpoint: >250° C.).

Example A2 Preparation of Intermediate 3

N-chlorosuccinimide (0.000327 mol) was added portion wise at roomtemperature to Intermediate 1 (0.000273 mol) in CH₃CN (5 ml). Themixture was stirred at room temperature for 4 hours. The precipitate wasfiltered, washed with CH₃CN and dried. Yielding: 0.065 g (59%, meltingpoint: >250° C.).

Example A3 Preparation of Intermediate 4

The same procedure as in example A1 was used, starting from2-fluoro-6-chloro analog of Intermediate 1 (0.000128 mol) andN-bromosuccinimide (0.000154 mol) in CH₃CN (5 ml), yielding: 0.037 g ofIntermediate 4 (62%, melting point: 236° C.)

Example A4 Preparation of Intermediates 5, 6, 7

A mixture of 2,4-dichloro-5-nitro-pyrimidine (0.0516 mol) and4-(2-cyanoethenyl)-2,6-dimethylphenylamine (0.0516 mol) were stirred at140° C. in an oil bath for 45 minutes, then poured in a mixture of waterand K₂CO₃ 10%. The precipitate was filtered and the filtrate extractedwith CH₂Cl₂. The organic layer was dried over magnesium sulfate,filtered and the solvent evaporated. The residue was purified by columnchromatography over silica gel (eluent: CH₂Cl₂ 100; 35-70 μm). The purefractions were collected and the solvent evaporated, yielding: 6.0 g ofIntermediate 5 (35%, melting point: >250° C.).

Preparation of Intermediate 6

A mixture of Intermediate 5 (0.0182 mol) and 4-cyanoaniline (0.0182 mol)were heated at fusion for 5 minutes, then poured in a mixture of waterand K₂CO₃ 10%. CH₂Cl₂ and a small quantity of MeOH were added and theprecipitate was filtered and dried. Yielding: 7.4 g of Intermediate 6(95%, melting point: >250° C.)

Preparation of Intermediate 7

A mixture of Intermediate 6 (0.0180 mol) and tin (II) chloride dihydrate(0.125 mol) in ethanol (100 ml) were stirred at 70° C. overnight, thenpoured in a mixture of water and K₂CO₃ 10%. The precipitate was filteredover celite. The filtrate was removed and the precipitate washed withCH₂Cl₂ and THF. The solvent was evaporated. Yield: 6.0 g of Intermediate7 (87%, melting point: >250° C.).

Example A5 Preparation of the 2-fluoro-6-chloro-phenyl Analogs ofIntermediates 5, 6 and 7

A mixture of 2,4-dichloro-5-nitro-pyrimidine (0.0153 mol) and4-(2-cyanoethenyl)-2-fluoro-6-chloro-phenylamine (0.0153 mol) wereheated at fusion for 5 minutes, then poured in a mixture of water andK₂CO₃ 10% and extracted with CH₂Cl₂. The organic layer was dried overmagnesium sulfate, filtered and the solvent evaporated. The residue waspurified by column chromatography over silica gel (eluent: CH₂Cl₂ 100;35-70 μm). The pure fractions were collected and the solvent evaporated.Yield: 1.9 g of2-chloro-4-[4-(2-cyanoethenyl)-2-fluoro-6-chloro-phenylamino]-5-nitro-pyrimidine,Intermediate 8 (35%, melting point: 217° C.).

A mixture of Intermediate 8 (0.000424 mol) and 4-cyanoaniline (0.000424mol) were heated at fusion for 5 minutes, then poured in a mixture ofwater and K₂CO₃ 10%. CH₂Cl₂ and a small quantity of MeOH were added andthe precipitate was filtered and dried. Yield: 1.34 g of4-[4-[4-(2-cyanoethenyl)-2-fluoro-6-chloro-phenylamino]-5-nitro-pyrimidine]amino]benzonitrile,Intermediate 9 (73%, melting point: >250° C.)

A mixture of Intermediate 9 (0.00306 mol) and tin (II) chloridedihydrate (0.0214 mol) in ethanol (20 ml) were stirred at 70° C.overnight, then poured in a mixture of water and K₂CO₃ 10%. Theprecipitate was filtered over celite. The filtrate was removed and theprecipitate washed with CH₂Cl₂ and THF. The solvent was evaporated.Yield: 1.1 g of4-[4-[4-(2-cyanoethenyl)-2-fluoro-6-chloro-phenylamino]-5-aminopyrimidine]amino]benzonitrile,Intermediate 10 (89%, melting point: >250° C.).

Example A6 Preparation of Intermediate 11

A mixture of intermediate 2 (0.0112 mol),dichlorobis(triphenylphosphine)-palladium(II) (0.00228 mol), sodiumformate (0.0336 mol) and magnesium sulfate (1 g) in DMF (50 ml) werestirred at 100° C. for 20 hours under 8 bars pressure of carbonmonoxide. The mixture was filtered over celite and poured in water. Theprecipitate was filtered off, washed with water and Et₂O and dried.Yield: 2.9 g. of intermediate 11 (65%, melting point: >250° C.).

Example A7 Preparation of Intermediate 12

Sodium borohydride was added portionwise at 0° C. to intermediate 11(0.000254 mol) in THF (5 ml) and EtOH (3 ml). The mixture was stirred atroom temperature for 15 min. The mixture was poured in water andextracted with CH₂Cl₂. The organic layer was dried over magnesiumsulfate, filtered and the solvent evaporated. The residue wascrystallized from acetone, filtered off and dried. Yield: 0.045 g (45%,melting point >250° C.) of Intermediate 12.

Example A8 Preparation of Intermediate 13

A mixture of intermediate 11 (0.000254 mol) and hydroxylaminehydrochloride (0.000380 mol) in pyridine (3 ml) was stirred at roomtemperature for 20 hours, then poured in water. The precipitate wasfiltered off, washed with water and Et₂O and dried. Yield: 0.048 g. ofintermediate 13 (39%, melting point: >250° C.).

Example B1 Preparation of Compound 2

A few drops of acetic acid was added to a mixture at room temperature ofcyanoborohybride on solid support (0.00042 mol), Intermediate 7 (0.00021mol) and 3-pyridinecarboxaldehyde (0.000315 mol) in acetonitrile (5 ml).The mixture was stirred at room temperature for 40 hours and thenfiltered. The mixture was poured in water and K₂CO₃ 10% and extractedwith CH₂Cl₂. The organic layer was dried over magnesium sulfate,filtered and the solvent evaporated. The residue was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/MeOH/NH₄OH 97/3/0.1; 10μm). The pure fractions were collected and the solvent evaporated.Yielding: 0.041 g. This fraction was crystallized fromdiisopropyl-ethylether. The precipitate was filtered off and dried.Yield: 0.034 g of compound 2 (34%, melting point: 140° C.).

Second Method:

In this method, 3 equivalents of sodium cyanoborohybride instead ofcyanoborohybride on solid support were used and the mixture was stirredat room temperature overnight.

Example B2 Preparation of Compound 64

Two drops of acetic acid was added at room temperature to a mixture ofsodium cyanoborohybride (0.00114 mol), intermediate 11 (0.000380 mol)and 3-(aminomethyl)-pyridine (0.000570 mol) in THF (5 ml). The mixturewas stirred at room temperature for 20 hours. The mixture was poured inwater and K₂CO₃ 10% and extracted with CH₂Cl₂. The organic layer wasdried over magnesium sulfate, filtered and the solvent evaporated. Theresidue was purified by column chromatography over silica gel (eluent:CH₂Cl₂ 100; Kromasil 5 μm). The pure fractions were collected and thesolvent evaporated. Yield: 0.066 g of compound 64 (36%, melting point:236° C.).

Example B3 Preparation of Compound 72

A mixture of intermediate 11 (0.000254 mol) and o-benzylhydroxylaminehydrochloride (0.000380 mol) in pyridine (3 ml) was stirred at roomtemperature for 20 hours, then poured in water. The precipitate wasfiltered off, washed with water and Et₂O and dried. Yield: 0.082 g. ofCompound 72 (65%, melting point: 99° C.).

Example B4 Preparation of Compound 75

A mixture of intermediate 13 (0.000244 mol), 4-chloromethylthiazolehydrochloride (0.000269 mol) and potassium carbonate (0.000488 mol) inDMF (3 ml) was stirred at room temperature for 20 hours, and then pouredin water. The precipitate was filtered off, washed with water and Et₂Oand dried. The residue was purified by column chromatography over silicagel (eluent: CH₂Cl₂ 100 to CH₂Cl₂/MeOH 98/2; Kromasil 5 μm). The purefractions were collected and the solvent evaporated. Yield: 0.051 g ofcompound 75 (41%, melting point: >250° C.).

Example B5 Preparation of Compound 82

Sodium cyanoborohybride (0.00050 mol) was added at room temperature to amixture of Compound 1 (0.000167 mol) and paraformaldehyde (0.000500 mol)in acetonitrile (10 ml). Few drops of acetic acid were added and themixture was stirred at room temperature overnight. The mixture waspoured in water and K₂CO₃ 10% and extracted with CH₂Cl₂. The organiclayer was dried over magnesium sulfate, filtered and the solventevaporated. The residue was purified by column chromatography oversilica gel (eluent: CH₂Cl₂ 100 to CH₂Cl₂/MeOH 95/5; Kromasil 5 μm). Thepure fractions were collected and the solvent evaporated. Yield: 0.028 gof compound 82 (34%, melting point: 216° C.).

Example B6 Preparation of Compound 84

A few drops of acetic acid was added to a mixture at room temperature ofsodium cyanoborohybride (0.00119 mol), intermediate 7 (0.000393 mol) and2-methoxycinnamaldehyde (0.000413 mol) in acetonitrile (8 ml). Themixture was stirred at room temperature for 40 hours. The mixture waspoured in water and K₂CO₃ 10% and extracted with CH₂Cl₂. The organiclayer was dried over magnesium sulfate, filtered and the solventevaporated. The residue was purified by column chromatography oversilica gel (eluent: CH₂Cl₂/AcOEt 95/5; Kromasil 5 μm). The purefractions were collected and the solvent evaporated. Yielding: 0.010 gof compound 84 (5%, melting point: 118° C.).

Tables 1-6 list compounds that were or can be prepared according to theabove Examples (Ex. No.).

TABLE 1

Phys. Data and Co. nr Example R⁴ R^(4a) R^(5a) stereo-chemistry 1 B1 CH₃CH₃

(E) 228° C. 2 B1 CH₃ CH₃ 3-pyridinyl (E/Z) 96/4 140° C. 3 B1 CH₃ CH₃2-furanyl (E)/253° C. 4 B1 CH₃ CH₃ 3-furanyl (E) 236° C. 5 B1 CH₃ CH₃2-methoxyphenyl (E)/230- 237° C. 6 B1 CH₃ CH₃

(E) 114° C. 7 B1 CH₃ CH₃ 2-pyridinyl (E)/>250° C. 8 B1 CH₃ CH₃

(E) 9 B1 CH₃ CH₃ 2-fluorophenyl (E)/230° C. 10 B1 CH₃ CH₃6-bromo-2-pyridinyl (E)/131° C. 11 B1 CH₃ CH₃ phenyl (E)/221° C. 12 B1CH₃ CH₃

(E) 113° C./114° C. 13 B1 CH₃ CH₃ 2-thienyl (E)/250° C. 14 B1 CH₃ CH₃2,6-dimethoxyphenyl (E)/227° C. 15 B1 CH₃ CH₃ 3-thienyl (E) 16 B1 CH₃CH₃ 2-chlorophenyl (E)/221 ° C. 17 B1 CH₃ CH₃ 2-methylphenyl (E)/218° C.18 B1 CH₃ CH₃

(E) 167° C. 19 B1 CH₃ CH₃ 5-chloro-2-furanyl (E)/231° C. 20 B1 CH₃ CH₃2-(trifluoromethyl)phenyl (E)/231° C. 21 B1 CH₃ CH₃ 5-methyl-2-thienyl(E)/199° C. 22 B1 CH₃ CH₃ 5-ethyl-2-thienyl (E)/95° C. 23 B1 CH₃ CH₃

(E/Z)97/3 >250° C. 24 B1 CH₃ CH₃ 5-bromo-2-furanyl (E) 217° C. 25 B1 CH₃CH₃ 5-methyl-2 furanyl (E) 26 B1 CH₃ CH₃ 2-phenoxy-5-pyridin-3-yl(E)/118° C. 27 B1 CH₃ CH₃

(E) 154° C. 28 B1 CH₃ CH₃ 5-[3-(trifluoromethyl)phenyl]- (E)/131° C.2-furanyl 29 B1 CH₃ CH₃ 3-(trifluoromethyl)phenyl (E)/107° C. 30 B1 CH₃CH₃ 4-(trifluoromethyl)phenyl (E)/114° C. 31 B1 CH₃ CH₃5-(3-chlorophenyl)-2-furanyl (E)/116° C. 32 B1 CH₃ CH₃ 4-chlorophenyl(E)/130° C. 33 B1 CH₃ CH₃ 5-phenyl-2-furanyl (E)/112° C. 34 B1 CH₃ CH₃4-(phenylmethoxy)phenyl (E)/104° C. 35 B1 CH₃ CH₃5-(4-bromophenyl)-2-furanyl (E)/118° C. 36 B1 CH₃ CH₃ 3-(phenoxy)phenyl(E)/170° C. 37 B1 CH₃ CH₃

(E)/163° C. 38 B1 CH₃ CH₃ 5-(4-chlorophenyl)-2-furanyl (E)/177° C. 39 B1CH₃ CH₃ 2-benzofuranyl (E)/149° C. 40 B1 CH₃ CH₃ 4-phenoxyphenyl(E)/113° C. 41 B1 CH₃ CH₃ 5-(2,4-dichlorophenyl)-2- (F)/172° C. furanyl42 B1 CH₃ CH₃ 4-phenyl-2-thienyl (E)/127° C. 43 B1 CH₃ CH₃5-methyl-3-phenyl-4-isoxazolyl (E)/>250° C. 44 B1 CH₃ CH₃5-phenyl-2-thienyl (E)/113° C. 45 B1 CH₃ CH₃

(E)/209° C. 46 B1 CH₃ CH₃

(E)/132° C. 47 B1 CH₃ CH₃

(E)/250° C. 48 B1 CH₃ CH₃

(E)/>250° C. 49 B1 CH₃ CH₃

(E)/109° C. 50 B1 CH₃ CH₃

(E)/>250° C. 51 B1 CH₃ CH₃

(E)/115° C. 52 B1 CH₃ CH₃

(E)/149° C. 53 B1 CH₃ CH₃

(E)/>250° C. 54 B1 CH₃ CH₃

(E)/224° C. 55 B1 CH₃ CH₃

(E)/103° C. 56 B1 CH₃ CH₃

(E)/125° C. 57 B1 CH₃ CH₃

(E)/228° C. 58 B1 CH₃ CH₃

(E)/233° C. 59 B1 CH₃ CH₃

(E)/165° C.

TABLE 2

Comp. No. Example R⁴ R^(4a) R^(5b) Phys. data 60 B2 CH₃ CH₃ 2-pyridyl(E) 209° C. 61 B2 CH₃ CH₃ 5-methyl-2-furanyl (E) 187° C. 62 B2 CH₃ CH₃4-pyridyl (E) >250° C. 63 B2 CH₃ CH₃ 2-furanyl (E) 228° C. 64 B2 CH₃ CH₃3-pyridyl (E) 236° C. 65 B2 CH₃ CH₃ 2-thienyl (E) 219° C. 66 B2 CH₃ CH₃

(E/Z:98/2) 175° C. 67 B2 CH₃ CH₃

(E) 94° C. 68 B2 CH₃ CH₃

(E) 205° C. 69 B2 CH₃ CH₃

(E/Z:90/10) 206° C. 70 B2 CH₃ CH₃

(E/Z:96/4) 150° C.

TABLE 3

Phys. Data and stereo- Comp. nr Example R^(5c) chemistry 71 B3

(E) 167° C. 72 B3

(E) 99° C. 73 B4

(E) 232° C. 74 B4

(E) >250° C. 75 B4

(E) >250° C. 76 B4

(E) >250° C. 77 B4

(E) 118° C. 78 B4

(E) 150° C. 79 B4

(E) 242° C. 80 B4

(E) 239° C. 81 B4

(E) >250° C.

TABLE 4

Phys. Data and stereo- Comp. nr Example R^(5e) chemistry 82 B5

(E) 216° C. 83 B5

(E) 223° C.

TABLE 5

Phys. Data and stereo- Comp. nr Example R^(5e) chemistry 84 B6

(E/E) 118° C. 85 B6

(E/E) 116° C. 86 B6

(E/E) 116° C. 87 B6

(E/E) 130° C. 88 B6

(E/E) 140° C.

TABLE 6

Comp. Phys. Data and nr Example R⁴ R^(4a) R^(5f) stereo-chemistry 89 B2CH₃ CH₃

(E) 123° C.

Formulation Examples

Capsules

A compound of formula (I) is dissolved in organic solvent such asethanol, methanol or methylene chloride, preferably, a mixture ofethanol and methylene chloride. Polymers such as polyvinylpyrrolidonecopolymer with vinyl acetate (PVP-VA) or hydroxypropylmethylcellulose(HPMC), typically 5 mPa.s, are dissolved in organic solvents such asethanol, methanol methylene chloride. Suitably the polymer is dissolvedin ethanol. The polymer and compound solutions are mixed andsubsequently spray dried. The ratio of compound/polymer is selected from1/1 to 1/6. Intermediate ranges can be 1/1.5 and 1/3. A suitable ratiocan be 1/6. The spray-dried powder, a solid dispersion, is subsequentlyfilled in capsules for administration. The drug load in one capsuleranges between 50 and 100 mg depending on the capsule size used.

Film-Coated Tablets

Preparation of Tablet Core

A mixture of 100 g of a compound of formula (I), 570 g lactose and 200 gstarch is mixed well and thereafter humidified with a solution of 5 gsodium dodecyl sulfate and 10 g polyvinylpyrrolidone in about 200 ml ofwater. The wet powder mixture is sieved, dried and sieved again. Thenthere is added 100 g microcrystalline cellulose and 15 g hydrogenatedvegetable oil. The whole is mixed well and compressed into tablets,giving 10.000 tablets, each comprising 10 mg of the active ingredient.

Coating

To a solution of 10 g methylcellulose in 75 ml of denaturated ethanolthere is added a solution of 5 g of ethylcellulose in 150 ml ofdichloromethane. Then there is added 75 ml of dichloromethane and 2.5 ml1,2,3-propanetriol. 10 g of polyethylene glycol is molten and dissolvedin 75 ml of dichloromethane. The latter solution is added to the formerand then there is added 2.5 g of magnesium octadecanoate, 5 g ofpolyvinylpyrrolidone and 30 ml of concentrated color suspension and thewhole is homogenized. The tablet cores are coated with the thus obtainedmixture in a coating apparatus.

Antiviral Spectrum:

Because of the increasing emergence of drug resistant HIV strains, thepresent compounds were tested for their potency against clinicallyisolated HIV strains harboring several mutations. These mutations areassociated with resistance to reverse transcriptase inhibitors andresult in viruses that show various degrees of phenotypiccross-resistance to the currently commercially available drugs such asfor instance AZT and delavirdine.

The antiviral activity of the compound of the present invention has beenevaluated in the presence of wild type HIV and HIV mutants bearingmutations at the reverse transcriptase gene. The activity of thecompounds is evaluated using a cellular assay and the residual activityis expressed in pEC₅₀ values. The columns IIIB and A-G in the table listthe pEC₅₀ values against various strains IIIB, A-G.

-   Strain IIIB is wild type HIV-LAI strain-   Strain A contains mutation Y181C in HIV reverse transcriptase,-   Strain B contains mutation K103N in HIV reverse transcriptase,-   Strain C contains mutation L100I in HIV reverse transcriptase,-   Strain D contains mutation Y188L in HIV reverse transcriptase,-   Strain E contains mutations L100I and K103N in HIV reverse    transcriptase,-   Strain F contains mutations K103N and Y181C in HIV reverse    transcriptase, and-   Strain G contains mutations L100I, K103N, Y181C, V179I, Y181C,    E138G, V179I, L2214F, V278V/I and A327A/V in HIV reverse    transcriptase.

Compound number IIIB A B C D E F G 1 8.9 8.3 9 8.7 8.1 8.2 8.6 6.8 3 7.88 8.1 8.1 7.9 7.5 7.4 5

1. A compound of formula

a N-oxide, a pharmaceutically acceptable addition salt, or astereochemically isomeric form thereof, wherein n is 0, 1, 2, 3; m is 0,1, 2, 3; each R¹ independently is hydrogen; aryl; formyl;C₁₋₆alkylcarbonyl; C₁₋₆alkyl; C₁₋₆alkyloxycarbonyl; C₁₋₆alkylsubstituted with formyl, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl, orwith C₁₋₆alkylcarbonyloxy; each R² independently is hydroxy; halo;C₁₋₆alkyl; C₁₋₆alkyloxycarbonyl; R^(2a) is cyano; aminocarbonyl; amino;C₁₋₆alkyl; halo; C₁₋₆alkyloxy X₁ is —NR¹—, —O—, —C(═O)—, —CH₂—, —CHOH—,—S—, —S(═O)r; R³ is C₁₋₆alkyl substituted with cyano R⁴ is halo;hydroxy; C₁₋₆alkyl; C₁₋₆alkyloxy; cyano; nitro; polyhaloC₁₋₆alkyl;C₁₋₆alkyloxycarbonyl; amino; mono- or di(C₁₋₄alkyl)amino; R⁵ is aradical of formula —Y-Alk-L, -Alk′-Y-L or -Alk′-Y-Alk-L; each Alk orAlk′ independently is a bivalent C₁₋₆alkyl or C₂₋₆alkenyl group; L isaryl or Het; Y is O, S, —S(═O)_(r)—, NR¹; —CH═N—O—; Het is a 5- or6-membered completely unsaturated ring system wherein one, two, three orfour ring members are hetero atoms each independently selected from thegroup consisting of nitrogen, oxygen and sulfur, and wherein theremaining ring members are carbon atoms; and, where possible, anynitrogen ring member may optionally be substituted with C₁₋₆alkyl; whichring system may optionally be annelated with a benzene ring; and whereinany ring carbon atom, including any carbon of an optionally annelatedbenzene ring, may, each independently, optionally be substituted with asubstituent selected from halo, hydroxy, mercapto, cyano, C₁₋₆alkyl,hydroxyC₁₋₄alkyl, carboxyC₁₋₄alkyl, C₁₋₄alkyloxyC₁₋₄alkyl,C₁₋₄alkyloxycarbonylC₁₋₄alkyl, cyanoC₁₋₄alkyl, mono- anddi(C₁₋₄alkyl)aminoC₁₋₄alkyl, Het¹C₁₋₄alkyl, arylC₁₋₄alkyl,polyhaloC₁₋₄alkyl, C₃₋₇cycloalkyl, C₂₋₆alkenyl, aryl-C₂₋₄alkenyl,C₁₋₄alkyloxy, —OCONH₂, polyhaloC₁₋₄alkyloxy, aryloxy, amino, mono- anddi-C₁₋₄alkylamino, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,4-C₁₋₆alkylpiperazinyl, C₁₋₄alkylcarbonylamino, formyl,C₁₋₄alkylcarbonyl, C₁₋₄alkyloxy-carbonyl, aminocarbonyl, mono- anddiC₁₋₄alkylaminocarbonyl, aryl, Het¹; Het¹ is pyridyl, thienyl, furanyl,oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, thiadiazolyl,oxadiazolyl quinolinyl, benzothienyl, benzofuranyl; which each mayoptionally be substituted with one or two C₁₋₄alkyl radicals; Q ishydrogen, C₁₋₆alkyl, halo, polyhaloC₁₋₆alkyl, or —NR⁹R¹⁰; R⁹ and R¹⁰each independently are hydrogen; C₁₋₆alkyl each aryl is phenyl or phenylsubstituted with one, two, three, four or five substituents eachindependently selected from halo, hydroxy, mercapto, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, hydroxyC₁₋₆alkyl, aminoC₁₋₆alkyl, mono ordi(C₁₋₆alkyl)aminoC₁₋₆alkyl, C₁₋₆alkylcarbonyl, C₃₋₇cycloalkyl,C₁₋₆alkyloxy, phenylC₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, aminosulfonyl,C₁₋₆alkylthio, cyano, nitro, polyhaloC₁₋₆alkyl, polyhaloC₁₋₆alkyloxy,aminocarbonyl, phenyl, Het¹.
 2. A compound according to claim 1 whereinHet is a heterocycle selected from pyrrolyl, furanyl, thienyl,pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,triazolyl, tetrazolyl, thiatriazolyl, thiadiazolyl oxadiazolyl, pyridyl,pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothienyl,benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, indolyl,benzothiadiazolyl, benzofurazanyl, benzoxadiazolyl, indazolyl,quinolinyl, said heterocycle optionally being substituted on its carbonatoms with one, two or three substituents each independently selectedfrom halo, hydroxy, mercapto, cyano, C₁₋₆alkyl, hydroxyC₁₋₄alkyl,carboxyC₁₋₄alkyl, C₁₋₄alkyloxyC₁₋₄alkyl, C₁₋₄alkyloxycarbonyl-C₁₋₄alkyl,cyanoC₁₋₄alkyl, mono- and di(C₁₋₄alkyl)aminoC₁₋₄alkyl, Het C₁₋₄alkyl,arylC₁₋₄alkyl, polyhaloC₁₋₄alkyl, C₃₋₇cycloalkyl, arylC₂₋₄alkenyl,C₁₋₄alkyloxy, —OCONH₂, polyhaloC₁₋₄alkyloxy, aryloxy, amino, mono- anddi-C₁₋₄alkylamino, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,4-C₁₋₆alkylpiperazinyl, C₁₋₄alkylcarbonylamino, formyl,C₁₋₄alkylcarbonyl, aryl, C₁₋₄alkyloxycarbonyl, aminocarbonyl, mono- anddiC₁₋₄alkylaminocarbonyl, Het¹.
 3. A compound according to claim 1wherein Het is a heterocycle selected from pyrrolyl, furanyl, thienyl,pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,triazolyl, tetrazolyl, thiatriazolyl, to thiadiazolyl oxadiazolyl,pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, indolyl,benzothiadiazolyl, quinolinyl, said heterocycle optionally beingsubstituted on its carbon atoms with one, two or three substituents eachindependently selected from halo, hydroxy, cyano, C₁₋₆alkyl,C₁₋₄alkyloxycarbonyl-C₁₋₄alkyl, amino, mono- and di-C₁₋₄alkylamino,morpholinyl, C₁₋₄alkylcarbonylamino, aminocarbonyl, mono- anddiC₁₋₄alkylaminocarbonyl, aryl, Het¹.
 4. A compound according to claim 1wherein Het is a heterocycle selected from pyrrolyl, furanyl, thienyl,oxadiazolyl, pyridyl, said heterocycle optionally being substituted onits carbon atoms with one, two or three substituents each independentlyselected from halo, hydroxy, C₁₋₆alkyl, phenyl, Het¹ (the latter inparticular being pyridyl).
 5. A compound according to claim 1 wherein nis 0, 1 or 2; m is 0, 1 or 2; R¹ is hydrogen; or C₁₋₆alkyl; R² ishydroxy; halo; C₁₋₆alkyl cyano; nitro; amino; mono- ordi(C₁₋₆alkyl)amino; trifluoromethyl; R^(2a) is cyano; aminocarbonyl;amino; C₁₋₆alkyl; halo; C₁₋₆alkyloxy X₁ is —NR¹—, —O—, —S—, —S(═O)r-; R³is C₂₋₆alkenyl substituted with cyano; R⁴ is halo; hydroxy; C₁₋₆alkylC₁₋₆alkyloxy; cyano; trifluoromethyl; Q is hydrogen or —NR⁹R¹⁰.
 6. Acompound according to claim 5 wherein R² is halo, C₁₋₆alkyl R^(2a) ishalo, cyano, aminocarbonyl, C₁₋₆alkyl optionally substituted with cyanoor aminocarbonyl, C₂₋₆alkenyl; X₁ is —NH—, —N(CH₃)—, —O—, —S—; R⁴ ishalo, C₁₋₄alkyl, C₁₋₄alkyloxy, or cyano; Y is O, NR¹; —CH═N—O—; Q ishydrogen, amino, mono- or di-C₁₋₄alkylamino.
 7. A compound according toclaim 1 wherein the compound has the formula


8. A pharmaceutical composition comprising a pharmaceutically acceptablecarrier and as active ingredient a therapeutically effective amount of acompound as claimed in claim
 1. 9. A compound according to claim 1wherein R⁵ is a radical of formula —Y—C_(p)H_(2p)-L or—C_(q)H_(2q)—Y—C_(p)H_(2p)-L; wherein L is aryl or Het; and p is 1-6; qis 1-6.
 10. A compound according to claim 9 wherein Y is O, S, NR¹;—CH═N—O—; p is 1-4; q is 1-4.
 11. A compound according to claim 10wherein Y is NR¹ or —CH═N—O—; p is 1-2; q is 1-2.
 12. A compoundaccording to claim 4 wherein Het¹ is pyridyl.
 13. A compound accordingto claim 6 wherein n is 0; m is 2; R⁴ is halo or C₁₋₄alkyl; Q ishydrogen.
 14. A compound according to claim 13 wherein R⁵ is a radicalof formula —Y—C_(p)H_(2p)-L or —C_(q)H_(2q)—Y—C_(p)H_(2p)-L; wherein Lis aryl or Het; and p is 1-6; q is 1-6.
 15. A compound according toclaim 14 wherein Y is O, S, NR¹; —CH═N—O—; p is 1-4; q is 1-4.
 16. Acompound according to claim 15 wherein Y is NR¹ or —CH═N—O—; p is 1-2; qis 1-2.
 17. A compound according to claim 16 wherein Het is aheterocycle selected from pyrrolyl, furanyl, thienyl, oxadiazolyl,pyridyl, said heterocycle optionally being substituted on its carbonatoms with one, two or three substituents each independently selectedfrom halo, hydroxy, C₁₋₆alkyl, phenyl, Het¹.
 18. A compound according toclaim 17 wherein Het¹ is pyridyl.